scholarly journals Platelet Activation Mechanisms and Consequences of Immune Thrombocytopenia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3386
Author(s):  
Siyu Sun ◽  
Rolf T. Urbanus ◽  
Hugo ten Cate ◽  
Philip G. de Groot ◽  
Bas de Laat ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Autoimmune Disorders ◽  
Common Mechanism ◽  
Platelet Activity ◽  
Bleeding Events ◽  
Drug Induced ◽  
Elevated Liver Enzymes ◽  
Increased Risk

Autoimmune disorders are often associated with low platelet count or thrombocytopenia. In immune-induced thrombocytopenia (IIT), a common mechanism is increased platelet activity, which can have an increased risk of thrombosis. In addition, or alternatively, auto-antibodies suppress platelet formation or augment platelet clearance. Effects of the auto-antibodies are linked to the unique structural and functional characteristics of platelets. Conversely, prior platelet activation may contribute to the innate and adaptive immune responses. Extensive interplay between platelets, coagulation and complement activation processes may aggravate the pathology. Here, we present an overview of the reported molecular causes and consequences of IIT in the most common forms of autoimmune disorders. These include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), drug-induced thrombocytopenia (DITP), heparin-induced thrombocytopenia (HIT), COVID-19 vaccine-induced thrombosis with thrombocytopenia (VITT), thrombotic thrombocytopenia purpura (TTP), and hemolysis, the elevated liver enzymes and low platelet (HELLP) syndrome. We focus on the platelet receptors that bind auto-antibodies, the immune complexes, damage-associated molecular patterns (DAMPs) and complement factors. In addition, we review how circulating platelets serve as a reservoir of immunomodulatory molecules. By this update on the molecular mechanisms and the roles of platelets in the pathogenesis of autoimmune diseases, we highlight platelet-based pathways that can predispose for thrombocytopenia and are linked thrombotic or bleeding events.

The Frequency of Rheumatic Disease Autoantibodies in Patients with ADAMTS13-Deficient Thrombotic Thrombocytopenia Purpura (TTP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2090-2090
Author(s):  
Karen K. Swisher ◽  
Qurana F. Lewis ◽  
Judith A. James ◽  
Johanna A. Kremer Hovinga ◽  
Bernhard Lämmle ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Plasma Exchange ◽  
Potential Risk ◽  
Lupus Erythematosus ◽  
Autoimmune Disorders ◽  
First Episode ◽  
Adamts13 Activity ◽  
Disease Systemic Lupus Erythematosus ◽  
Increased Risk ◽  
Adamts13 Deficiency

Abstract Patients who have TTP associated with acquired, severe ADAMTS13 deficiency have an autoimmune etiology and therefore may have increased risk for additional autoimmune disorders. The Oklahoma TTP-HUS Registry enrolled 247 consecutive patients with their first episode of clinically diagnosed TTP from 11-13-1995 (the date of our initial ADAMTS13 measurement) to 6-30-2006 for whom plasma exchange treatment was requested; ADAMTS13 activity was measured in 228 (92%) of patients immediately before their first plasma exchange treatment; 42 (18%) patients had ADAMTS13 activity <10%. Three patients were excluded from this analysis because of preexisting systemic rheumatic disease (systemic lupus erythematosus (SLE), 2, Sjogren’s syndrome, 1). To examine the potential risk for development of autoimmune disorders, we measured screening autoantibodies (ANA, dsDNA, Sm, nRNP, Ro, La, ribosomal P, Jo-1, anti-phospholipid (aPL) IgG and IgM) in 34 of the 39 (87%) remaining patients. The median age at initial presentation was 39 years (range 9–71 years); 27 (79%) patients were women; 13 (41%) patients were black. Autoantibodies were measured by indirect immunofluorescence, immunodiffusion, or ELISA. Measurements were performed only once in 16 patients; in 18 patients 2–3 measures were performed over a period of 13 to 126 months. Rheumatic disease autoantibodies TTP patients *1 patient had a maximum titer of >1:3240 in 2 samples; 1 patient developed overt SLE and his titer decreased with treatment. ANA ≥1:40 on at least one occasion 33/34 (97%) ANA ≥1:120 on at least one occasion 29/34 (85%) ANA measured ≥2 times, increasing titer 14/16* (88%) Anti-dsDNA ≥1:30 12/34 (35%) Anti-Ro positive 14/29 (48%) Anti-Sm positive 1/34 (3%) Anti-nRNP positive 1/34 (3%) aPL IgG and/or IgM ≥moderate positive 4/34 (12%) No patients had positive tests for anti-La, anti-Ribo-P, or anti-Jo-1. 23 (68%) of the 34 patients had a positive test for one or more rheumatic disease autoantibodies (dsDNA, nRNP, Ro, La, or moderately positive aPLs). 4 of the 34 patients died during their initial episode; the remaining 30 patients have been followed for a median of 6.4 years (range, 1–11.5 years). During this time only 1 patient has developed clinically evident SLE; no other patients have developed systemic rheumatic diseases. Conclusions: A high prevalence of rheumatic disease-associated autoantibodies were found in a cohort of consecutive patients with TTP associated with acquired severe ADAMTS13 deficiency. The presence of dsDNA and Ro autoantibodies and increasing ANA titers suggest that patients with ADAMTS13-deficientTTP may have a potential risk for developing additional autoimmune disorders such as SLE or Sjogren’s syndromes. [3] These serologic observations support clinical observations that presenting features of TTP and SLE may overlap.

scholarly journals Capecitabine-Induced Subacute Cutaneous Lupus Erythematosus in a Patient with Systemic Lupus Erythematosus

2018 ◽  
Vol 2 (1) ◽  
pp. 59-63
Author(s):  
Alyx Rosen ◽  
Evan Darwin ◽  
Jennifer N Choi
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Cutaneous Lupus Erythematosus ◽  
Metastatic Breast ◽  
Subacute Cutaneous Lupus Erythematosus ◽  
Systemic Lupus ◽  
Drug Induced ◽  
Increased Risk ◽  
History Of ◽  
Cutaneous Lupus

Capecitabine is a fluoropyrimidine chemotherapy prodrug of 5-fluorouracil (5-FU) used in the treatment of metastatic breast and colorectal cancers. Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) is a rare side effect of capecitabine therapy, with eight cases previously reported. We report a case of DI-SCLE in a patient with a documented history of systemic lupus erythematosus (SLE). This is the second documented case of DI-SCLE in a patient with a past medical history of SLE, and provides evidence that there may be an increased risk of DI-SCLE in these patients. Further research should examine whether patients with SLE are at greater risk for this adverse event. 

scholarly journals Platelet Activation and Platelet–Leukocyte Aggregates in Type I Diabetes Mellitus

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 230S-239S ◽  
Author(s):  
Asmaa M. Zahran ◽  
Omnia El-Badawy ◽  
Ismail L. Mohamad ◽  
Deiaaeldin M. Tamer ◽  
Safwat M. Abdel-Aziz ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Type I Diabetes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Control Group ◽  
Type I ◽  
Platelet Activity ◽  
Increased Risk

Hyperglycemia alone may not explain the increased risk of cardiovascular diseases (CVDs) in patients with type 1 diabetes (T1D) compared with type 2. This study emphases on the evaluation of some platelet activity markers in patients with T1D, with relevance to some metabolic disorders as hyperlipidemia and hyperglycemia. This study was performed on 35 patients with T1D and 20 healthy controls. All participants were subjected to full history taking, clinical examination and assay of glycated hemoglobin (HbA1c), and lipid profile. The expression of CD62P and CD36 on platelets and the frequency of platelet–monocyte, and platelet–neutrophil aggregates were assessed by flow cytometry. Patients showed significantly higher expression of CD62P and CD36 than the control group. Platelets aggregates with monocytes were also higher among patients than the control group. Levels of CD36+ platelets, CD62P+ platelets, and platelet–monocyte aggregates revealed significant correlations with the levels of HbA1c, total cholesterol, low-density lipoprotein, and triglycerides. Hyperlipidemia and hyperglycemia accompanying T1D have a stimulatory effect on platelet activation which probably makes those patients vulnerable to CVD than nondiabetics.

scholarly journals Finding the “switch” in platelet activation Prediction of key mediators involved in platelet hyperreactivity using a novel network biology approach

2021 ◽  
Author(s):  
TP Lemmens ◽  
DM Coenen ◽  
ICL Niessen ◽  
F Swieringa ◽  
SLM Coort ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Molecular Mechanisms ◽  
Shape Change ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Network Biology ◽  
Small Gtpases ◽  
Platelet Activity

Abstract The healthy endothelium controls platelet activity through release of prostaglandin I2 (PGI2) and nitric oxide. The loss of this natural brake on platelet activity can cause platelets to become hyperreactive. PGI2 attenuates platelet activation by adenosine diphosphate (ADP) through stimulation of cyclic adenosine monophosphate (cAMP) production and subsequent phosphorylation changes by protein kinase A (PKA). We hypothesize that proteins/processes involved in platelet hyperactivity downstream of the cAMP-PKA pathway can serve as a “switch” in platelet activation and inhibition. We designed a network biology approach to explore the entangled platelet signaling pathways downstream of PGI2 and ADP. The STRING database was used to build a protein-protein interaction network from proteins of interest in which we integrate a quantitative platelet proteome dataset with pathway information, relative RNA expression of hematopoietic cells, the likelihood of the proteins being phosphorylated by PKA, and drug-target information from DrugBank in a biological network. We distilled 30 proteins from existing phosphoproteomics datasets (PXD000242 and PXD001189) that putatively can be “turned on” after ADP-mediated platelet activation and subsequently switched “off” after platelet inhibition with iloprost. Enrichment analysis revealed biological processes related to vesicle secretion and cytoskeletal reorganization to be overrepresented coinciding with topological clusters in the network. Our method highlights novel proteins related to vesicle transport, platelet shape change, and small GTPases as potential switch proteins in platelet activation and inhibition. Our novel approach demonstrates the benefit of data integration by combining tools and datasets and visualization to obtain a more complete picture of complex molecular mechanisms.

Abstract 53: Role of Serotonin through 5HT 2A in alphaIIbBeta3 Outside-in Activation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Kendra H Oliver ◽  
Matthew Duvernay ◽  
Heidi E Hamm ◽  
Ana M Carneiro
Keyword(s):  
Platelet Activation ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Critical Role ◽  
Surface Expression ◽  
Clear Understanding ◽  
Storage Site ◽  
Platelet Activity ◽  
Increased Risk ◽  
Receptor Surface Expression

Patients taking selective serotonin reuptake inhibitors (SSRIs) have an increased risk of bleeding. However it remains unclear how SSRIs, which inhibit the serotonin transporter (SERT), modulate hemostasis, particularly platelet activation. 5HT (serotonin, 5-hydroxytryptamine) is taken up by platelets via SERT and activates the 5HT 2A receptor. αIIbβ3 is an integrin that binds fibrinogen and plays a critical role in platelet aggregation, which is central to hemostasis and thrombosis. Futhermore, it is known that αIIbβ3 and SERT interact genetically, physically, and functionally. To gain a clear understanding of how SERT function regulates platelet activity we examined two independent models of SERT inhibition - constitutive genetic deletion (SERT -/- ) and 6-day water citalopram administration. Through SERT, platelets are the major storage site for 5HT in whole blood. Our works suggests that ADP-mediated αIIbβ3 activation is decreased as assessed by JON/a binding. Additionally while 5HT alone does not cause any platelet activation in SERT +/+ , 5HT synergizes with submaximal ADP to potentiate αIIbβ3 activation. The synergy of 5HT-ADP synergy is lost in SERT -/- platelets as determined by the addition of exogenous 5HT. Furthermore, blocking 5HT 2A receptor with an antagonist, ketanserin, inhibited ADP-mediated αIIbβ3 activation, suggesting that 5HT-ADP synergy could be mediated through activation of the 5HT 2A receptor. Additionally, we found that 5HT 2A receptor surface expression was reduced in SERT -/- platelets. SERT -/- platelet membranes incubated with a 5HT 2A agonist, DOI, also exhibited reduced 35S GTPys incorporation. These findings suggest that long-term inhibition of SERT leads to reduced 5HT 2A receptor-dependent potentiation of αIIbβ3 activation, perhaps through altered hemostatic regulation of 5HT. Further experiments are being carried out to determine a possible novel regulation of αIIbβ3 via 5HT 2A that could alter the functionality of αIIbβ3. However, these findings suggest a novel mechanism central to the increased bleeding observed in patients taking SSRIs and support the continued investigation of 5HT 2A receptor inhibitor as anti-platelet drugs for treatment of cardiovascular diseases.

Platelet Activation by a Humanized Monoclonal CD40 Ligand (CD40L) Antibody.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1516-1516
Author(s):  
Todd Meyer ◽  
Ali Amirkhosravi ◽  
Theresa Robson ◽  
Mildred Amaya ◽  
Desai Hina ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Lupus Erythematosus ◽  
Flow Cytometric Analysis ◽  
Molar Ratio ◽  
Dependent Manner ◽  
Thromboembolic Events ◽  
Platelet Factor ◽  
Increased Risk

Abstract Monoclonal antibodies are increasingly used as therapeutics, and some (anti-VEGF, anti-CD40L) have produced unexpected thrombotic side effects. For example, clinical trials with the humanized monoclonal CD40L antibody, hu5c8, in patients with systemic lupus erythematosus (SLE, a chronic inflammatory autoimmune disease) were prematurely terminated due to thromboembolic events. In SLE, elevated soluble CD40L (sCD40L) antigen levels may indicate in vivo platelet activation, putting patients at increased risk for thrombosis. We therefore hypothesized that anti-CD40L immunotherapy may represent an additional prothrombotic hit, leading to clinical manifestation of thromboembolic disease in patients with SLE. In this report, we provide experimental evidence that hu5c8, when combined with homotrimeric recombinant human sCD40L (rhsCD40L) in 1:3 molar ratio to allow formation of higher-order immune complexes (IC), activates platelets in an FcγRIIA-dependent manner. In a washed platelet system, IC formed of rhsCD40L (5 μg/mL) with hu5c8 (15 μg/mL) strongly induced platelet aggregation, while IC of rhsCD40L with hu5c8-Fab or hu5c8-F(ab’)2 did not. Similarly, IC of rhsCD40L with hu5c8-agly, an aglycosylated hu5c8 variant with reduced Fc domain binding to the low affinity platelet IgG receptor, FcγRIIA (CD32), failed to induce aggregation. FcγRIIA dependency was further demonstrated with the monoclonal CD32 antibody, IV.3. These results suggest that hu5c8-mediated platelet activation requires both antigen (CD40L) and the IgG Fc domain. Flow cytometric analysis of P-selectin (CD62P) confirmed that IC of rhsCD40L with hu5c8, but not with Fab, F(ab’)2, or hu5c8-agly, strongly activated platelets via FcγRIIA. When washed platelets were first sensitized with ADP, resulting in surface exposure of endogenous CD40L and sub-maximal aggregation of 5–25%, hu5c8 (10 μg/mL) induced strong platelet aggregation of up to 80–100% in the absence of exogenous rhsCD40L, indicating that physiologic levels of CD40L were sufficient for hu5c8-mediated platelet activation. ADP-sensitized platelets did not respond to equimolar concentrations of Fab, F(ab’)2, or hu5c8-agly. In the serotonin release assay (SRA), which is used for the detection of FcγRIIA-activating heparin-platelet factor 4 (PF4) autoantibodies in patients with heparin-induced thrombocytopenia (HIT), the experimental procedure generates close platelet-platelet contacts and causes release of α-granule proteins such as CD62P, PF4, and CD40L. In the absence of rhsCD40L, hu5c8, but not Fab, F(ab’)2, or hu5c8-agly, induced significant dense granule release, suggesting that exogenous rhsCD40L was not an absolute requirement for hu5c8-mediated platelet activation. In summary, our results show that the humanized monoclonal CD40L antibody, hu5c8, can strongly activate platelets in an Fc domain-dependent manner and that physiologically released CD40L is sufficient for this activity. This mechanism of activation is similar to that of HIT, in which homotetrameric PF4 released from prestimulated platelets provides the molecular basis for clustering of, and signaling through, FcγRIIA, resulting in a vicious cycle of platelet activation. Because thrombosis is a serious complication of HIT, it is reasonable to speculate that hu5c8-mediated platelet activation contributed to the pathophysiology of thromboembolic events in SLE patients receiving anti-CD40L immunotherapy.

scholarly journals A Case of Pancytopenia with Many Possible Causes: How Do You Tell Which is the Right One?

2019 ◽  
Author(s):  
Priscila Diaz ◽  
Mariana Abreu Vieira ◽  
António Carneiro ◽  
Natália Fernandes
Keyword(s):  
Lupus Erythematosus ◽  
Opportunistic Infections ◽  
Unknown Origin ◽  
Diagnostic Challenge ◽  
Drug Induced ◽  
Increased Risk ◽  
Immunosuppressed Patients ◽  
Recent Diagnosis ◽  
Severe Pancytopenia ◽  
The Right

Systemic lupus erythematosus (SLE) often presents with cytopenia(s); however, pancytopenia is found less commonly, requiring the consideration of possible aetiologies other than the primary disease. The authors describe the case of a female patient with a recent diagnosis of SLE admitted through the Emergency Department with fever of unknown origin and severe pancytopenia. She was medicated with prednisolone, hydroxychloroquine, azathioprine, amlodipine and sildenafil. Extensive investigation suggested azathioprine-induced myelotoxicity. However, the patient was found to have a concomitant cytomegalovirus (CMV) infection, with oral lesions, positive CMV viral load as well as the previously described haematological findings. Pancytopenia is always a diagnostic challenge, with drug-induced myelotoxicity, especially secondary to azathioprine, being a rare aetiology. This report reiterates the importance of the differential diagnosis of pancytopenia, especially in immunosuppressed patients with increased risk for opportunistic infections.

scholarly journals Understanding the Effects of Antipsychotics on Appetite Control

2022 ◽  
Vol 8 ◽  
Author(s):  
Sayani Mukherjee ◽  
Silje Skrede ◽  
Edward Milbank ◽  
Ramaroson Andriantsitohaina ◽  
Miguel López ◽  
...  
Keyword(s):  
Side Effects ◽  
Receptor Binding ◽  
First Generation ◽  
Antipsychotic Drugs ◽  
Molecular Mechanisms ◽  
Extrapyramidal Side Effects ◽  
Appetite Control ◽  
Drug Induced ◽  
Increased Risk

Antipsychotic drugs (APDs) represent a cornerstone in the treatment of schizophrenia and other psychoses. The effectiveness of the first generation (typical) APDs are hampered by so-called extrapyramidal side effects, and they have gradually been replaced by second (atypical) and third-generation APDs, with less extrapyramidal side effects and, in some cases, improved efficacy. However, the use of many of the current APDs has been limited due to their propensity to stimulate appetite, weight gain, and increased risk for developing type 2 diabetes and cardiovascular disease in this patient group. The mechanisms behind the appetite-stimulating effects of the various APDs are not fully elucidated, partly because their diverse receptor binding profiles may affect different downstream pathways. It is critical to identify the molecular mechanisms underlying drug-induced hyperphagia, both because this may lead to the development of new APDs, with lower appetite-stimulating effects but also because such insight may provide new knowledge about appetite regulation in general. Hence, in this review, we discuss the receptor binding profile of various APDs in relation to the potential mechanisms by which they affect appetite.

scholarly journals Longitudinal profiling of human blood transcriptome in healthy and lupus pregnancy

2019 ◽  
Vol 216 (5) ◽  
pp. 1154-1169 ◽  
Author(s):  
Seunghee Hong ◽  
Romain Banchereau ◽  
Bat-Sheva L. Maslow ◽  
Marta M. Guerra ◽  
Jacob Cardenas ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Embryo Implantation ◽  
Adverse Outcomes ◽  
Healthy Women ◽  
Cell Counts ◽  
Increased Risk ◽  
Pregnancy And Postpartum ◽  
Blood Transcriptome

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4+ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes.

Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1951-1957 ◽  
Author(s):  
Christian Lood ◽  
Stefan Amisten ◽  
Birgitta Gullstrand ◽  
Andreas Jönsen ◽  
Maria Allhorn ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Protein Expression ◽  
Vascular Disease ◽  
Platelet Activation ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Increased Risk

AbstractPatients with systemic lupus erythematosus (SLE) have a markedly increased risk to develop cardiovascular disease, and traditional cardiovascular risk factors fail to account for this increased risk. We used microarray to probe the platelet transcriptome in patients with SLE and healthy controls, and the gene and protein expression of a subset of differentially expressed genes was further investigated and correlated to platelet activation status. Real-time PCR was used to confirm a type I interferon (IFN) gene signature in patients with SLE, and the IFN-regulated proteins PRKRA, IFITM1 and CD69 (P < .0001) were found to be up-regulated in platelets from SLE patients compared with healthy volunteers. Notably, patients with a history of vascular disease had increased expression of type I IFN-regulated proteins as well as more activated platelets compared with patients without vascular disease. We suggest that interferogenic immune complexes stimulate production of IFNα that up-regulates the megakaryocytic type I IFN-regulated genes and proteins. This could affect platelet activation and contribute to development of vascular disease in SLE. In addition, platelets with type I IFN signature could be a novel marker for vascular disease in SLE.

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