Platelet activation and reactivity in a large cohort of patients with Gaucher disease

2021 ◽  
Author(s):  
Shoshana Revel-Vilk ◽  
Mira Naamad ◽  
Dafna Frydman ◽  
Michael R. Freund ◽  
Tama Dinur ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Platelet Function ◽  
Gaucher Disease ◽  
P Value ◽  
Bleeding Tendency ◽  
Platelet Dysfunction ◽  
Platelet Surface ◽  
Increased Risk ◽  
Αiibβ3 Integrin ◽  
Cd63 Expression

Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data. Methods: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients. Results: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r 0.17, p-value 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (-2 SD of reference range) was found in 79 (53%, 95% CI 44%-61%) patients, of whom 10 (6.7%, 95% CI 3.3%-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (OR (95% CI), 1.05 (1.01-1.1)) and low P-selectin reactivity (OR (95% CI), 2.03 (1.25-3.35)) were associated with more than one bleeding manifestation. Conclusion: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.

scholarly journals Predictors of mortality in adult patients with dengue: a study from South India

2018 ◽  
Vol 6 (5) ◽  
pp. 1605 ◽  
Author(s):  
Vasudeva Acharya ◽  
Mohammed Fahad Khan ◽  
Srinivas Kosuru ◽  
Sneha Mallya
Keyword(s):  
Renal Failure ◽  
Prothrombin Time ◽  
Tertiary Care ◽  
P Value ◽  
Bleeding Tendency ◽  
Care Hospital ◽  
Laboratory Parameters ◽  
Prolonged Prothrombin Time ◽  
Risk Of Death ◽  
Increased Risk

Background: Dengue is one of the important causes of acute febrile illnesses in India. Dengue can be a fatal disease, however there are no reliable markers which can predict mortality among these patients.Methods: A prospective cross sectional study was done in patients who were admitted to a tertiary care hospital with features of dengue fever. A total of 364 patients with IgM dengue serology positive were included in the study. Relevant clinical and laboratory parameters were collected from all patients. Association between clinico-laboratory parameters with mortality was studied using appropriate statistical methods.Results: Among the 364 patients recruited in this study, 14 (3.85%) patients died. Mortality among patients with age group 18-40 years was 2.04%, in patients aged above 40 years was 7.56%. Mortality among patients with hypotension was 42.42% (14 out of 33), bleeding manifestations was 15.38% (8/52), platelets <20,000/mm3 was 10.41% (10/96), ALT >200 was 13.04% (6/46), AST>200 was 12.34% (10/81), prolonged prothrombin time was 60%(12/20), renal failure was 28%(14/50), encephalopathy was 31.57% (6/19), multi organ dysfunction syndrome(MODS) was 43.33% (13/30), acute respiratory distress syndrome (ARDS) was 45.45% (5/11), pleural effusion was 7.5% (6/80).Conclusions: The overall mortality in the present study was 3.85%. Following variables were associated with increased risk of death among the dengue patients: Age >40 years, presence of hypotension, platelets <20000 cells/mm3, ALT>200U/L, AST>200U/L, prolonged prothrombin time, presence of renal failure, encephalopathy, MODS, ARDS and bleeding tendency (p value <0.05). Early identification of factors associated with mortality can help to make appropriate decision on care required.

scholarly journals Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib

2017 ◽  
Vol 1 (26) ◽  
pp. 2610-2623 ◽  
Author(s):  
Alexander P. Bye ◽  
Amanda J. Unsworth ◽  
Michael J. Desborough ◽  
Catherine A. T. Hildyard ◽  
Niamh Appleby ◽  
...  
Keyword(s):  
Platelet Function ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Critical Role ◽  
Platelet Dysfunction ◽  
Non Hodgkin Lymphoma ◽  
Healthy Donors ◽  
Increased Risk ◽  
Btk Inhibitor ◽  
Size And Morphology

Abstract The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII.

Immune Thrombocytopenia in Type I Gaucher Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3200-3200 ◽  
Author(s):  
Hanna Rosenbaum ◽  
Tina Napso ◽  
Lilach Bonstein
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Immune Modulation ◽  
Hematological Parameters ◽  
Autoimmune Disorder ◽  
Type I ◽  
Bleeding Tendency ◽  
Platelet Surface ◽  
Platelet Counts ◽  
Enzyme Replacement

Abstract Backgound: Type I Gaucher disease (GD) the non-neuronopathic form is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and/or infiltration of bone marrow by the lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in treated GD patients within 12–24 months of treatment. In GD patients, including ERT treated, with persistent low platelet counts other ethiological factors should be considered. Goals: To determine the etiology of persistent thrombocytopenia in Type I GD patients and to evaluate their clinical course and hematological parameters. Methods: Flow cytometric technique was used to detect platelet-surface associated IgG/M (PSIgG/M) in a cohort of 24 Type I GD patients followed at the Gaucher clinic in Haifa, Israel. The evaluated hematological parameters of the thrombocytopenic GD patients include: bleeding phenomena, concurrence of autoimmune phenomena, hematological malignancies and bone marrow findings. Results: Twenty four Type I GD patients, 15 females and 9 males with an age range of 35 to 80 years (median 53 years) were included in the study. Seventeen of the evaluated 24 patients were thrombocytopenic with platelet counts less than <100×109/l and 7/24 were in the normal range. Bone marrow aspirate was performed in 16 of the 17 thrombocytopenic patients and showed normal or hyperplasic megakariopoiesis together with Gaucher cells infiltrates. Six of the 17 thrombocytopenic patients received ERT for at least 24 months with no effect on the low platelet counts. Elevated platelet surface IgG was detected in 16/17(94%) of GD patients with thrombocytopenia and in only 1/7 (14%) of non thrombocytopenic patients (p<0.0001). In 6/17 of the thrombocytopenic patients, surface IgM (PSIgM) was found, in addition to the PSIgG. Those six patients are known with monoclonal IgM (concomitant Waldenstrom macroglobulinemia), markedly elevated polyclonal IgM levels, or lupus like autoimmune disorder which may have been responsible for the positive PSIgM. Only three thrombocytopenic patients with platelet counts less than 40×109/l had bleeding tendency (mainly purpura) with no response to steroid treatment (two of them were also resistant to ERT concerning their thrombocytopenia). Conclusions: Thrombocytopenia in Type I GD is related to either infiltration of bone marrow compromising megakariopoiesis or hypersplenism, but immune factors should also be considered. Despite the lack of response to steroids, the observed megakaryocytic hyperplasia in Gaucher infiltrated marrows, the failure to respond to ERT, and the presence of platelet surface antibodies in the thrombocytopenic patients, strongly implicate autoimmune etiology. The present study demonstrates that surface platelet antibodies may play a role in refractory thrombocytopenic GD patients. Since the role of splenectomy is controversial in GD, immune modulation approach should be considered.

A Study of Platelet Activation during Human Cardiopulmonary Bypass and the Effect of S-Nitrosoglutathione

1997 ◽  
Vol 78 (06) ◽  
pp. 1516-1519 ◽  
Author(s):  
Edward J Langford ◽  
Andrew Parfitt ◽  
Adam J de Beider ◽  
Michael T Marrinan ◽  
John F Martin
Keyword(s):  
Nitric Oxide ◽  
Flow Cytometry ◽  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Platelet Activation ◽  
Surface Expression ◽  
Platelet Inhibition ◽  
Nitric Oxide Donor ◽  
Platelet Dysfunction ◽  
Platelet Surface

SummaryCardiac surgery is complicated by the occurrence of post-operative bleeding due to platelet dysfunction. This is largely caused by platelet activation and consumption during cardiopulmonary bypass. Patients undergoing cardiac surgery requiring cardiopulmonary bypass were studied to determine whether early platelet changes due to bypass could be inhibited using the platelet-selective nitric oxide donor S-nitroso-glutathione (GSNO). Flow cytometry was used to measure platelet surface expression of P-selectin (an α-granule protein) and glycoproteins (GP) IIb/IIIa and Ib (mediators of aggregation and adhesion) before and 5 and 10 min after commencing cardiopulmonary bypass, in 6 controls and 6 patients receiving GSNO 50 μg/min. Platelet P-selectin expression increased during bypass both in controls and patients receiving GSNO. Glycoproteins IIb/IIIa and Ib fell during bypass in control and GSNO-treated patients. There was no difference between control and GSNO-treated groups. Thus no significant platelet inhibition by S-nitrosoglutathione was demonstrated under these conditions.

Decreased platelet reactivity identified by whole blood flow cytometry in Fanconi anaemia patients

2007 ◽  
Vol 98 (12) ◽  
pp. 1291-1297 ◽  
Author(s):  
Susanne Holzhauer ◽  
Ana-Gabriela Sitaru ◽  
Wolfram Ebell ◽  
Detlev Schindler ◽  
Helmut Hanenberg ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Blood Flow ◽  
Platelet Function ◽  
Whole Blood ◽  
Platelet Reactivity ◽  
Bone Marrow Failure ◽  
Receptor Expression ◽  
Platelet Glycoprotein ◽  
Bleeding Tendency ◽  
Reticulated Platelets

Summarydisorder characterized by congenital anomalies and a high risk for bone marrow failure and cancer. Bleeding is a frequent complication in FA, leading to substantial morbidity and mortality. Thrombocytopenia is a major factor leading to this complication, but the bleeding tendency of FA patients often exceeds what one might expect based on their platelet counts. We therefore investigated if alterations of platelet function contribute to the bleeding tendency of FA patients. We assessed platelet function in 11 FA patients and 23 controls with whole blood flow cytometry. We analyzed the expression of platelet membrane glycoprotein receptors, reactivity of platelets to physiologic agonists and the proportion of young platelets. In FA patients platelet PAC-1 after stimulation with thrombin receptor activating peptide (TRAP) and adenosine diphosphate (ADP) were 15–70% lower than in controls. We found no or only minor differences of platelet glycoprotein receptor expression between groups. While the proportion of reticulated platelets was not different, the absolute number of reticulated platelets was markedly lower in FA patients. Our data show that FA is associated with reduced platelet reactivity, which may contribute to the high bleeding tendency in FA patients. Whole blood flow cytometry is a suitable method for analysis of platelet function in FA patients.

In Vivo Effects of Eltrombopag on Human Platelet Function.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1301-1301 ◽  
Author(s):  
Bethan Psaila ◽  
James B. Bussel ◽  
Matthew D. Linden ◽  
You Fu Li ◽  
Marc R. Barnard ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Blood Flow ◽  
Platelet Count ◽  
Platelet Activation ◽  
Platelet Function ◽  
Whole Blood ◽  
Adult Patients ◽  
Platelet Surface ◽  
Integrin Αiibβ3

Abstract Eltrombopag, an orally-administered small-molecule agonist of the thrombopoietin receptor (c-Mpl), is under investigation as a treatment for immune thrombocytopenic purpura (ITP). Studies have indicated that eltrombopag does not ‘prime’ platelets for activation in vitro, and eltrombopag administration to healthy volunteers does not increase platelet surface P-selectin or activated integrin αIIbβ3 (Jenkins J. Blood 2007). However, the effects of eltrombopag on platelet function in thrombocytopenic patients in vivo, either by direct binding to c-Mpl receptors on platelets or indirectly by altering the dynamics of platelet production and causing an influx of young, large platelets, is unknown. Whole blood flow cytometry, unlike other assays of platelet function, enables measurement of platelet function in the setting of marked thrombocytopenia (Michelson. Platelets, Elsevier, 2007). As a substudy of larger treatment studies, 17 adult patients with chronic ITP received eltrombopag at a starting dose of 50 mg daily, with the possibility of an increase to 75 mg daily after 3 weeks. Blood samples were drawn pre-treatment, and after 7 and 28 days of therapy. Platelet count, mean platelet volume (MPV), and the immature platelet fraction (IPF, or reticulated platelet count) were measured using a Sysmex XE-2100. Platelet surface P-selectin and activated integrin αIIbβ3 (reported by monoclonal antibody PAC1) were measured by whole blood flow cytometry in the presence and absence of 0.5 μM ADP, 20 μM ADP, 1.5 μM thrombin receptor activating peptide (TRAP), or 20 μM TRAP. Bleeding was quantified by a comprehensive scale that allocates grades of 0 (no), 1 (minor) or 2 (marked) bleeding at 10 anatomical sites according to physical examination and/or history (Page, L.K. Br J Haematol 2007). Eleven of the 17 patients responded to eltrombopag with a rise in platelet count of >30 x 109/L. The IPF increased in responders but not non-responders (table 1). Response to eltrombopag was not predicted by pretreatment MPV or IPF. The ITP bleeding score decreased in responders over the study period in parallel with the increases in platelet count (table 1). As determined by platelet surface P-selectin and activated integrin αIIbβ3, eltrombopag did not result in platelet activation or augment ADP- or TRAP-induced platelet activation (table 2). In summary, eltrombopag increases the platelet count and reduces bleeding in responding adult patients with chronic ITP through the release of new platelets into the circulation. While bleeding is reduced in responders, eltrombopag does not result in platelet activation or augmentation of platelet activation by ADP or TRAP. This suggests that the newer platelets released by eltrombopag stimulation are not hyper-functional (or are only transiently so prior to day 7). Table 1 IPF (maximum absolute change, mean ± SEM x 109/L) Number in whom bleeding decreased Responders 57.0 ± 22.4 8/11 Non-responders 3.3 ± 1.5 1/6 Table 2 Study Day 0 7 28 MFI, mean fluorescence intensity, *P <0.05 compared with day 0 Activated αIIbβ3 MFI No agonist 11.4 11.3 9.2 Low ADP 180.3 159.4 98.4 High ADP 451.2 348.2* 251.8* Low TRAP 158.1 175.5 143.9 High TRAP 385.2 347.0 299.6 P-selectin MFI No agonist 5.5 6.6 6.2 Low ADP 48.6 43.4 38.8 High ADP 144.5 109.0 96.8 Low TRAP 113.8 114.9 107.8 High TRAP 457.3 396.3 330.9

Bleeding Tendency and Impaired Platelet Function In a Patient Carrying a Heterozygous Mutation In Thromboxane A2 Receptor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2524-2524
Author(s):  
Tsuyoshi Kamae ◽  
Kazunobu Kiyomizu ◽  
Tsuyoshi Nakazawa ◽  
Seiji Tadokoro ◽  
Shigenori Honda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Novel Mutation ◽  
Thromboxane A2 ◽  
Nucleotide Sequence Analysis ◽  
Heterozygous Mutation ◽  
Bleeding Tendency ◽  
Platelet Dysfunction ◽  
Functional Abnormality ◽  
Nasal Bleeding

Abstract Abstract 2524 Characterization of inherited platelet function disorders has revealed critical molecules and receptors for hemostasis and thrombosis. Thromboxane A2 (TXA2) is one of the major platelet agonists, and thromboxane A2 receptors (TP) are seven transmembrane small G protein coupled receptor. There are two isoforms, α and β, which differ only their C-terminus. TPα is mainly expressed in platelet. In general, platelet receptor abnormalities such as Glanzmann thrombasthenia and P2Y12 deficiency are inherited in an autosomal recessive manner. In other words, a subject carrying a heterozygous mutation does not show any platelet functional abnormality. In this study, we examined a patient with bleeding tendency and platelet dysfunction, and demonstrated that the patient is heterozygous for a novel mutation in TP, G insertion at nt.167-8. The proband (OSP-2) was a 7-year-old Japanese girl, and had repeated nasal bleeding and mild purpura from 3 years old. The nasal bleeding was sometimes severe and continued for 1 hour to be stopped. She was born from non-consanguineous parents. She was referred to Osaka University Hospital because of suspected platelet dysfunction. There were no abnormalities in blood cell counts and coagulation. Bleeding time was slightly prolonged (7.5 minutes) and ADP-induced platelet aggregation was impaired. U46619 (2.5 mM)-induced platelet aggregation was remarkably impaired in the proband. The impaired platelet aggregation was still observed even at high concentration of U46619 (10 mM). Essentially the same platelet functional abnormality was observed in her father. Informed consent was obtained from the patient and her family members. We firstly confirmed that there is no abnormality in the expression of platelet glycoproteins such as αIIbβ3, GPIb-IX, GPVI and GPIa. Nucleotide sequence analysis of TP cDNA obtained from the proband revealed a novel mutation, G insertion between nt.167 and nt.168 leading to a frame shift. No other mutation was detected in the coding region of TP. Sequencing of genomic DNA showed that the mutation was heterozygous in her father as well as the proband. Thus, the abnormal allele was inherited from her father. The wild-type TP expression construct or the mutant construct in pcDNA3.1 vector indicated that the expression of the mutant TP was markedly impaired. Consistent with molecular genetic analysis, immnoblotting with polyclonal antibody against cytoplasmic domain demonstrated that the amount of TP in platelets from the proband and her father were approximately half of controls. P-selectin expression as well as PAC-1 binding on platelets obtained from the proband was markedly impaired when stimulated with U46619 but not with 0.5 U/ml thrombin or 20 μM ADP. Essentially the same defects were obtained in platelets from her father. To evaluate more precisely the dynamic changes in the αIIbβ3 activation, we performed initial velocity analysis for PAC-1 binding. In brief, FITC-PAC-1 was added to the activated platelets at the indicated time points after stimulation and incubated for only 30 s. Interestingly, we detected PAC-1 binding about 36∼42% of control on platelets from the proband and her father at 5 sec after stimulation with 5μM U46619. However, at 1 min and 5 min PAC1 binding velocity rapidly decreased, suggesting that the sustained αIIbβ3 activation rather than initiation of αIIbβ3 activation was impaired. Consistent with these data, Rap1 activation at 10 sec, 1 min and 5 min after stimulation of U46610 were 50%, 17%, and 11% of control, respectively. We have shown that the P2Y12 plays a critical role in the sustained αIIbβ3 activation (T Kamae, et al. J Thromb Haemost 2006; 4:1379–87) From these data, we assume that the impaired αIIbβ3 activation may be due to a reduction in ADP release from the proband. Indeed, small amount of exogenous ADP (0.5μM) significantly improved the impaired αIIbβ3 activation induced by U46619. Our data demonstrate that the impaired platelet function to U46619 observed in the patient with heterozygous mutation in TP is, at least in part, due to a decrease in granular secretion, especially ADP. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Influence of Imidazole Carboxamide on Platelet Function

1977 ◽  
Author(s):  
P. Kubisz ◽  
P. Klener ◽  
S. Cronberg
Keyword(s):  
Platelet Function ◽  
Light Transmission ◽  
Platelet Rich Plasma ◽  
Cytostatic Drug ◽  
Bleeding Tendency ◽  
Platelet Dysfunction ◽  
Freezing And Thawing ◽  
Trade Name ◽  
Coagulation And Fibrinolysis

Imidazol carboxamide (DTIC, NSC-45388) is a cytostatic drug used in the treatment of malignant melanoma under the trade name of DacarbazinR, MSD. Its influence on platelet function, blood coagulation and fibrinolysis was investigated in vitro.At a concentration of 160 µg/ml it inhibited the increase in light transmission induced in platelet-rich plasma by standardized freezing and thawing. It also retarded the retraction of reptilase clots. This therefore indicated a stabilizing effect on the platelets at this dosage.At a concentration of 40 μg/ml the drug did not significantly influence the platelet function in vitro.This concentration corresponds to therapeutic plasma levels. At current dosage of the drug any bleeding tendency due to platelet dysfunction therefore seems unlikely.

scholarly journals Measurement of platelet p-selectin expression by flow cytometry in patients with acute ischemic stroke

2018 ◽  
Vol 18 (1) ◽  
pp. 14-20
Author(s):  
K Kalmarova ◽  
E Kurca ◽  
V Nosal ◽  
J Dluha ◽  
J Ballova ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Ischemic Stroke ◽  
Healthy Volunteers ◽  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
P Value ◽  
Platelet Surface ◽  
Antiplatelet Medication ◽  
Acute Cerebral Ischemia ◽  
The Difference

AbstractAims: The aim of this study was to asses the platelet activation in the acute phase of ischemic stroke and transient ischemic attack (TIA) by defining p-selectin (CD62) expression by flow cytometry in vivo – without stimulation with agonists. We also studied whether antiplatelet therapy supresses the levels of baseline p-selectin expression and verified if there is a correlation between platelet CD62 expression and the type of ischemic stroke.Methods: We determined the expression of platelet surface p-selectin using whole-blood flow cytometry within the first 48-hours after onset of cerebral symptoms in patients with atherothrombotic and lacunar ischemic stroke and in healthy volunteers. We studied the realationship between antiplatelet medication and the type of ischemic stroke to baseline p-selectin expression.Results: Patients with acute cerebral ischemia have an excess of circulating platelets that express p-selectin, compared to healthy volunteers. The difference between average p-selectin expression in the group of healthy volunteers and the group of patients with stroke was statistically significant (p-value < 0,000001). Patients with stroke without antiplatelet medication showed a higher p-selectin expression than patients with antiplatelet medication (ASA, CLP, or ASA and CLP), hovewer, the difference was not statistically significant. There is no relationship between CD62 expression and the type of stroke.Conclusions: We can conclude that p-selectin is a highly sensitive blood biomarker of increased platelet activation. Antiplatelet therapy suppresses baseline p-selectin expression only minimally, insignificantly according to our results.

scholarly journals Plasma Proteomic Profile Associated with Platelet Dysfunction after Trauma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Alexander E St. John ◽  
Yi Wang ◽  
Junmei Chen ◽  
Warren Osborn ◽  
Xu Wang ◽  
...  
Keyword(s):  
Platelet Function ◽  
Conflicts Of Interest ◽  
P Value ◽  
Horizontal Line ◽  
Type I ◽  
Severely Injured ◽  
Proteomic Profile ◽  
Platelet Dysfunction ◽  
Blood Draw ◽  
Volcano Plot

Background. Coagulopathic bleeding is a major cause of mortality after trauma, and platelet dysfunction contributes to this problem. The causes of platelet dysfunction are unknown, but a great deal can be learned from the plasma environment after injury, which may directly alter platelet function. Studying the changes in plasma using untargeted proteomics would provide unbiased insight into the presence of possible inhibitors of platelet function, changes to their major ligands, or other previously unknown pathways affecting platelet function. Methods. Citrated blood was collected from severely injured trauma patients at the time of their arrival to the Emergency Department. Platelet testing was performed immediately, and plasma was frozen for analysis. Samples were collected from 110 patients, and a subset of 24 patients was identified by a preserved (n=12) or severely impaired (n=12) platelet aggregation response to five different agonists (adenosine diphosphate, arachidonic acid, collagen, thrombin receptor-activating peptide, and ristocetin). Untargeted proteomics was performed by nanoflow liquid chromatography tandem mass spectrometry to determine the plasma protein profile associated with platelet dysfunction. Protein abundance levels for each patient were normalized to total protein concentration to control for hemodilution by crystalloid fluid infusion prior to blood draw. Results were compared by Wilcoxon rank-sum test, and a two-tailed p value less than 0.05 was considered significant. No adjustment was made for multiple comparisons, as the risk of a type II error was felt to outweigh that of a type I error in this exploratory analysis. Results. Patients with platelet dysfunction were more severely injured (median Injury Severity Score 29.5 vs. 13.5, p=0.002) but otherwise demographically similar to those with retained platelet function. Of 232 proteins identified, twelve were significantly different in the low- vs. high-platelet function groups: gelsolin (median peak intensity 9.70E+6 vs. 1.48 E+7, p=0.002), transketolase (2.86E+4 vs. 9.36E+3, p=0.003), protein S100-A8 (4.60E+4 vs. 2.64E+4, p=0.006) and -A9 (5.83E+4 vs. 4.07E+4, p=0.012), histone H4 (5.72E+4 vs. 8.47E+6, p=0.007), histidine-rich glycoprotein (HRG) (5.00E+6 vs. 8.30E+6, p=0.008), factor XIII B chain (1.09E+6 vs. 1.61E+6, p=0.020), apolipoprotein A-IV (2.30E+7 vs. 3.28E+7, p=0.024), alpha-enolase (1.02E+5 vs. 4.15E+4, p=0.024), heat shock protein 90-alpha (1.41E+4 vs. 4.08E+3, p=0.045), alpha-2-HS-glycoprotein (2.83E+7 vs. 3.68E+7, p=0.045), and neutrophil gelatinase-associated lipocalin (3.44E+4 vs. 1.36E+4, p=0.045). These results are summarized in the figure, which shows one group of proteins that decreased in abundance (on the left side of the volcano plot) and another that increased (on the right side) in the patients with low platelet function. The twelve proteins that changed the most fall into several categories related to platelet function. Low gelsolin and high histone levels are each associated with microvascular obstruction by release of intracellular material that accumulates in small vessels and activates platelets. Low HRG and high damage-associated molecular pattern (DAMP) protein levels are consistent with massive innate immune activation, which can impair platelet function in many ways. Conclusion. This study provides an unbiased description of the change in proteomic profile associated with platelet dysfunction after trauma and identifies twelve proteins with the most profound changes. The pathways involving these proteins are salient targets for immediate investigation to better understand platelet dysfunction after trauma and identify targets for intervention. Figure Legend. Volcano plot depicting fold-change and statistical significance of individual proteins in patients with low vs. high platelet function. Dotted horizontal line represents p = 0.05. Twelve proteins showed a statistically significant p value. Figure Disclosures No relevant conflicts of interest to declare.

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