scholarly journals Circulating Erythrocyte-Derived Microparticles Are Associated with Coagulation Activation in Sickle Cell Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 126-126 ◽  
Author(s):  
Eduard J. Beers van ◽  
M. C. Schaap ◽  
R.J. Berckmans ◽  
R. Nieuwland ◽  
A. Sturk ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Thrombin Generation ◽  
Absolute Difference ◽  
Glycophorin A ◽  
Cell Disease ◽  
Coagulation Activation ◽  
Factor Xi ◽  
The Absolute

Abstract Backgound: Sickle cell disease (SCD) is characterized by a hypercoagulable state involving multiple factors, including chronic hemolysis and circulating cell-derived microparticles (MPs). There is still no consensus on the cellular origin of such MPs and the exact mechanism by which they may support coagulation activation in SCD. Aim: In the present study, we aimed to analyze the origin of circulating MPs and their pro-coagulant phenotype in 25 consecutive SCD patients during painful crises and steady state. conditions Methods: MPs were identified by flowcytometry on basis of their size and density and on their ability to bind annexin V. Measurements were corrected for auto-fluorescence. Labeling with cell-specific monoclonal antibodies was corrected with isotype-matched control antibodies. For thrombin generation experiments patient derived MPs were reconstituted in defibrinated (reptilase-treated) normal pool (MP-free) plasma. For the inhibition experiments, the defibrinated plasma and the MPs were separately incubated with antibodies against coagulation factors VII or XI, or tissue factor pathway inhibitor (TFPI). Results: The majority of MPs originated from platelets (GPIIIa, CD61+: 86.1%) and erythrocytes (Glycophorin A, CD235+: 9.7%), and their numbers did not differ significantly between crisis and steady state. A distinct subset of transferrin receptor (CD71+)-exposing MPs was present, but neither MPs originating from monocytes (CD14+) nor endothelial cells (CD144+, CD146+, CD62E+) were detectable, and also no MPs exposing TF could be identified. The number of erythrocyte-derived MPs strongly correlated with plasma levels of hemolytic markers, i.e. hemoglobin (r=−0.58, P<0.001) and lactate dehydrogenase (r=0.59;P<0.001), von Willebrand factor as a marker of endothelial activation (r=0.44;P<0.001), and D-dimer and prothrombin fragment F1+2 (r=0.52;P<0.001 and r=0.59;P<0.001, respectively) as markers of fibrinolysis and coagulation activation. In the thrombin generation test, the total amount of thrombin generated (represented by the area under the curve (AUC) of the thrombin generation curve) correlated with the total number of circulating MPs (R=0.63, P<0.001). Thrombin generation was unaffected by pre-incubation with anti-human factor VII but increased slightly in the presence of anti-TFPI (16%; P=0.01) while the presence of anti-factor XI suppressed thrombin generation by about 50% (P<0.001). The extent of this inhibition (as a percentage of thrombin generation without antibody) was significantly correlated with the circulating number of erythrocyte-derived MPs (r=0.50, P=0.023), but not with platelet-derived MPs or reticulocyte-derived MPs. Also the absolute difference in thrombin generation between the experiments with and without factor XI antibody correlated with the absolute number of glycophorin A+ MPs (r=0.55, P=0.002). Conclusion: We conclude that the procoagulant state in SCD is, at least in part, due to the procoagulant effects of circulating erythrocyte-derived MPs. Their relation to the ability of anti-factor XI to block thrombin generation in SCD patients suggests an important role of factor XI-dependent thrombin generation in these patients.

The acceleration of the propagation phase of thrombin generation in patients with steady-state sickle cell disease is associated with circulating erythrocyte-derived microparticles

2012 ◽  
Vol 107 (06) ◽  
pp. 1044-1052 ◽  
Author(s):  
Grigoris Gerotziafas ◽  
Patrick Van Dreden ◽  
Mourad Chaari ◽  
Vassiliki Galea ◽  
Amir Khaterchi ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Thrombin Generation ◽  
Generation Process ◽  
Cell Disease ◽  
Significant Acceleration ◽  
High Concentrations ◽  
The Impact ◽  
Functional Alteration

SummarySickle cell disease (SCD) is linked to hypercoagulability and is characterised by high concentrations of erythrocyte-derived microparticles (Ed-MPs). However, the impact of procoagulant cell-derived microparticles on the thrombin generation process remains unclear. We analysed the alterations of each phase of thrombin generation (TG) in relation to the concentration of erythrocyte- or platelet-derived microparticles (Ed-MPs and Pd-MPs) in a cohort of patients with steady-state SCD. We studied 92 steady-state SCD patients, 19 of which were under treatment with hydroxyurea, and 30 healthy age- and sex-matched individuals. TG was assessed by calibrated automated thrombogram. Ed-MP and Pd-MP expressing or not phosphatidylserine (PS) were determined by means of flow cytometry. Procoagulant phospholipid-dependent activity in the plasma was evaluated by the Procoag-PPL assay. Levels of thrombomodulin and haemoglobin in the plasma as well as red blood cell and reticulocyte counts were measured. SCD patients, independently of the administration of hydroxyurea, were marked by a significant acceleration in the propagation phase of TG which correlated with the Ed-MP/PS+ concentration. TG was significantly attenuated in hydroxyurea-treated patients. In conclusion, the acceleration of the propagation phase of TG, driven by Ed-MP/PS+, is a major functional alteration in blood coagulation in patients with steady-state SCD. Treatment with hydroxyurea, in addition to the regulation of haemolysis, lowers Ed-MPs and attenuates thrombin generation. The thrombogram could be a useful tool for the diagnosis of hypercoagulability and optimisation of the treatment in patients with SCD.

Inflammation and Coagulation Activation Influence Clinical Disease Burden in Sickle Cell Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4812-4812
Author(s):  
Suba Krishnan ◽  
Yamaja Setty ◽  
Carlton Dampier ◽  
A. Koneti Rao ◽  
Marie Stuart
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Thrombin Generation ◽  
Endothelial Activation ◽  
Polymorphonuclear Neutrophils ◽  
Cell Disease ◽  
Coagulation Activation ◽  
Control Range ◽  
Clinical Events ◽  
Clinical Profiles

Abstract Background: Hemoglobin SC sickle cell disease (HbSC-SCD) manifests similar, but milder and less frequent clinical events than HbSS-SCD. Although the cause of such phenotypic variability is unclear, several lines of evidence point to the complex interplay of multiple etiologies in SCD pathology. Serum lactate dehydrogenase (LDH) has emerged as an important clinical surrogate for intravascular hemolysis in evaluating reduced nitric oxide (NO) bioavailability-mediated complications in SCD; most of the data comes from adult studies and shows that higher LDH levels in HbSS patients correlate clinically with pulmonary hypertension, priapism and leg ulcers. One recent publication showed that elevated LDH levels in pediatric HbSS correlate with abnormal transcranial Doppler values. In this study we compare biomarker and clinical profiles in children and adolescents with HbSS vs. HbSC disease with control-range LDH levels. We hypothesized that despite similar LDH levels as the HbSC patient group, HbSS patients would demonstrate marked differences in biomarker and clinical profiles that could implicate important additional pathways of disease mechanisms. Methods: 48 patients at steady state (age 3–20 years) with control-range LDH levels (<400 IU/l) were divided in two groups: HbSS (n=24) and Hb-SC (n=24). Laboratory evaluations included hematologic indices, and biomarkers pertinent to inflammation and endothelial activation (CRP, sVCAM1, sP-selectin, sE-selectin), and coagulation/fibrinolysis {DDimer, prothrombin fragment (f1.2), tissue plasminogen activator (tPA), Plasmin-antiplasmin complex (PAP), plasminogen activator inhibitor (PAI-1), and phosphatidylserine-positive microparticles (PS+ve MPs)}. Clinical charts were reviewed for microvascular occlusive events including total hospitalizations for VOC and ACS over a 3 year period to include year of study, the year previous to, and the year following date of study. t test was used to compare means (parametric and non-parametric as appropriate). Results: Biomarker (Units) HbSS Mean±SD; n=24 HbSC Mean±SD; n=24 P-value NB: Fibrinolytic markers and total RBC-phosphatidylserine values showed no statistical difference between groups (data not shown); also please note for comparison * CRP- 1-3mg/l is a biomarker for moderately increased risk of coronary vascular disease LDH (IU/l) 277±87 292±61 0.33 Hemoglobin 9.4±2.00 11.1±0.7 <0.001 Reticulocytes 8.5±6.1 2.7±1.07 0.002 Polymorphonuclear neutrophils 5965±3468 3634±1281 0.023 Monocytes 1057±578 519±282 <0.001 Platelets 491±179 302±68 <0.001 F1.2 (nM) 1.51±0.80 0.95±0.62 0.004 D-Dimer (μg/ml) 0.20±0.27 0.06±0.05 0.007 PS+ve Microparticles (per ml whole blood × 10−3) 515±380 490±573 0.897 sVCAM ng/ml 736±237 697±195 0.537 sP-Selectin ng/ml 71±27 44±8 0.004 sE-Selectin ng/ml 147±43 84±27 <0.001 CRP mg/l* 2.5±1.6 0.9±0.8 <0.001 Clinical Events (VOC + ACS over 3 yrs) 2±2.4 0.6±1.1 0.08 Summary: Our data indicate that HbSS children and adolescents with control-range LDH bear greater clinical burden of disease (more hospitalizations for VOC and ACS) as compared to HbSC patients with similar LDH levels (i.e. equivalent levels of intra-vascular hemolysis). The biomarker profile of “steady state” HbSS patients showed: Increased bone marrow (BM) turnover (higher reticulocytes, polymorphonuclear neutrophils, monocytes and platelets); Increased inflammation/endothelial activation (elevated CRP, sP-selectin and sE-selectin); and Coagulation activation (increased f1.2 and DDimers). However, there was no difference in PS+ve MPs between the HbSS and HbSC groups. While the increased BM activity supports a greater baseline hemoglobin in HbSS patients with control-range LDH, our data imply that this is not without cost. We suggest that this increase in neutrophils, monocytess and platelets plays a key role in influencing inflammation, endothelial activation and thrombin generation in the microvessel-dependent SCD complications of VOC and ACS. Contrary to our expectations, the increase in thrombin generation noted in our study does not appear to be influenced by the presence of PS+ve MPs. These data provide further evidence to support the study of therapeutic strategies targeting inflammation and coagulation in SCD.

scholarly journals Neutrophil gelatinase–associated lipocalin as a biomarker of nephropathy in sickle cell disease

2021 ◽  
Author(s):  
Rajaa Marouf ◽  
Adekunle D. Adekile ◽  
Hadeel El-Muzaini ◽  
Rasha Abdulla ◽  
Olusegun A. Mojiminiyi
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Roc Curve ◽  
Screening Tests ◽  
Cell Disease ◽  
Urine Ngal ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Plasma Ngal ◽  
Neutrophil Gelatinase

AbstractSickle cell nephropathy (SCN) develops via altered hemodynamics and acute kidney injury, but conventional screening tests remain normal until advanced stages. Early diagnostic biomarkers are needed so that preventive measures can be taken. This study evaluates the role of neutrophil gelatinase–associated lipocalin (NGAL) as a biomarker of SCN in steady state and vaso-occlusive crisis (VOC). In this case-control study, 74 sickle cell disease (SCD) patients (37 in steady state and 37 in VOC) and 53 control subjects had hematological and biochemical measurements including plasma and urine NGAL. Univariate and logistic regression analyses were used to find the associations between variables. The receiver operating characteristic (ROC) curve was used to determine the diagnostic performance characteristics of plasma and urine NGAL for detection of VOC. Plasma and urine NGAL, urine microalbumin:creatinine ratio, and urine protein:creatinine ratio were significantly higher in VOC. Microalbuminuria was present in 17.1% steady state and 32.0% VOC patients. Microalbuminuria showed significant correlations with age, plasma NGAL, WBC, and hemolytic parameters. Area under the ROC curve for plasma NGAL was 0.69 (95%CI = 0.567–0.813; p = 0.006) and 0.86 (95%CI = 0.756–0.954; p < 0.001) for urine NGAL. Urine NGAL cut-off value of 12.0 ng/mL had 95% sensitivity and 65% specificity. These results confirm the presence of nephropathy during VOC and suggest that plasma and urine NGAL would be useful in the identification of SCN. Urine NGAL should be used as the screening biomarker, and patients with VOC and urine NGAL > 12.0 ng/mL should be selected for aggressive management to prevent progression of renal damage.

scholarly journals Effects of Genotypes and Treatment on Oxygenscan Parameters in Sickle Cell Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 811
Author(s):  
Camille Boisson ◽  
Minke A. E. Rab ◽  
Elie Nader ◽  
Céline Renoux ◽  
Celeste Kanne ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Blood Cell ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Cell Disease ◽  
Oxygen Gradient ◽  
Acute Complication ◽  
Adults And Children ◽  
The Difference

(1) Background: The aim of the present study was to compare oxygen gradient ektacytometry parameters between sickle cell patients of different genotypes (SS, SC, and S/β+) or under different treatments (hydroxyurea or chronic red blood cell exchange). (2) Methods: Oxygen gradient ektacytometry was performed in 167 adults and children at steady state. In addition, five SS patients had oxygenscan measurements at steady state and during an acute complication requiring hospitalization. (3) Results: Red blood cell (RBC) deformability upon deoxygenation (EImin) and in normoxia (EImax) was increased, and the susceptibility of RBC to sickle upon deoxygenation was decreased in SC patients when compared to untreated SS patients older than 5 years old. SS patients under chronic red blood cell exchange had higher EImin and EImax and lower susceptibility of RBC to sickle upon deoxygenation compared to untreated SS patients, SS patients younger than 5 years old, and hydroxyurea-treated SS and SC patients. The susceptibility of RBC to sickle upon deoxygenation was increased in the five SS patients during acute complication compared to steady state, although the difference between steady state and acute complication was variable from one patient to another. (4) Conclusions: The present study demonstrates that oxygen gradient ektacytometry parameters are affected by sickle cell disease (SCD) genotype and treatment.

scholarly journals Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 597-602 ◽  
Author(s):  
GP Rodgers ◽  
MS Roy ◽  
CT Noguchi ◽  
AN Schechter
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Microvascular Obstruction ◽  
Controlled Study ◽  
Control Group ◽  
Cell Disease ◽  
Retinal Arteriolar

Abstract To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

Acute phase proteins and interleukins in steady state sickle cell disease

2009 ◽  
Vol 61 (1) ◽  
pp. 49-54 ◽  
Author(s):  
Konstantinos L. Bourantas ◽  
Georgios N. Dalekos ◽  
Alexandres Makis ◽  
Aristidis Chaidos ◽  
Stavroula Tsiara ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Cell Disease

scholarly journals Normal Non-HDL Cholesterol, Low Total Cholesterol, and HDL Cholesterol Levels in Sickle Cell Disease Patients in the Steady State: A Case-Control Study of Tema Metropolis

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Richard K. D. Ephraim ◽  
Patrick Adu ◽  
Edem Ake ◽  
Hope Agbodzakey ◽  
Prince Adoba ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Total Cholesterol ◽  
Sickle Cell ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Lipoprotein Cholesterol ◽  
Cell Disease ◽  
Cross Sectional

Background.Abnormal lipid homeostasis in sickle cell disease (SCD) is characterized by defects in plasma and erythrocyte lipids and may increase the risk of cardiovascular disease. This study assessed the lipid profile and non-HDL cholesterol level of SCD patients.Methods.A hospital-based cross-sectional study was conducted in 50 SCD patients, in the steady state, aged 8–28 years, attending the SCD clinic, and 50 healthy volunteers between the ages of 8–38 years. Serum lipids were determined by enzymatic methods and non-HDL cholesterol calculated by this formula: non-HDL-C = TC-HDL-C.Results.Total cholesterol (TC) (p=0.001) and high-density lipoprotein cholesterol (HDL-C) (p<0.0001) were significantly decreased in cases compared to controls. The levels of non-HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were similar among the participants. The levels of decrease in TC and HDL were associated with whether a patient was SCD-SS or SCD-SC. Systolic blood pressure and diastolic blood pressure were each significantly associated with increased VLDL [SBP,p=0.01, OR: 0.74 (CI: 0.6–0.93); DBP,p=0.023, OR: 1.45 (CI: 1.05–2.0)].Conclusion.Dyslipidemia is common among participants in this study. It was more pronounced in the SCD-SS than in SCD-SC. This dyslipidemia was associated with high VLDL as well as increased SBP and DBP.

scholarly journals Thrombin generation reveals high procoagulant potential in the plasma of sickle cell disease children

2011 ◽  
Vol 87 (2) ◽  
pp. 145-149 ◽  
Author(s):  
Denis F. Noubouossie ◽  
Phu Quoc Lê ◽  
Francis Corazza ◽  
France Debaugnies ◽  
Laurence Rozen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Thrombin Generation ◽  
Cell Disease

scholarly journals Hematological and Biochemical Reference Ranges for the Population with Sickle Cell Disease at Steady State in Tanzania

Hemato ◽  
2022 ◽  
Vol 3 (1) ◽  
pp. 82-97
Author(s):  
Anna Daniel Fome ◽  
Raphael Z. Sangeda ◽  
Emmanuel Balandya ◽  
Josephine Mgaya ◽  
Deogratius Soka ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
General Population ◽  
Sickle Cell ◽  
Age Groups ◽  
Mean Corpuscular Hemoglobin ◽  
Reference Ranges ◽  
Cell Disease ◽  
Laboratory Reference ◽  
Males And Females

Hematological and biochemical reference values in sickle cell disease (SCD) are crucial for patient management and the evaluation of interventions. This study was conducted at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania, to establish laboratory reference ranges among children and adults with SCD at steady state. Patients were grouped into five age groups and according to their sex. Aggregate functions were used to handle repeated measurements within the individual level in each age group. A nonparametric approach was used to smooth the curves, and a parametric approach was used to determine SCD normal ranges. Comparison between males and females and against the general population was documented. Data from 4422 patients collected from 2004–2015 were analyzed. The majority of the patients (35.41%) were children aged between 5–11 years. There were no significant differences (p ≥ 0.05) in mean corpuscular hemoglobin concentration (MCHC), lymphocytes, basophils, and direct bilirubin observed between males and females. Significant differences (p < 0.05) were observed in all selected parameters across age groups except with neutrophils and MCHC in adults, as well as platelets and alkaline phosphatase in infants when the SCD estimates were compared to the general population. The laboratory reference ranges in SCD at steady state were different from those of the general population and varied with sex and age. The established reference ranges for SCD at steady state will be helpful in the management and monitoring of the progress of SCD.

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