Low Mortality In Sickle Cell Patient Cohort with Elevated Tricuspid Regurgitant Jet Flow Velocity

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1641-1641
Author(s):  
Eduard J. Beers van ◽  
Charlotte F.J. Tuijn ◽  
Erfan Nur ◽  
Anita W. Rijneveld ◽  
M. R. Mac Gillavry ◽  
...  
Keyword(s):  
Risk Factor ◽  
Sickle Cell Disease ◽  
Mortality Rate ◽  
Pulmonary Function ◽  
Brain Natriuretic Peptide ◽  
Sickle Cell ◽  
Plasma Levels ◽  
Early Death ◽  
Cell Disease

Abstract Abstract 1641 Elevated tricuspid regurgitant jet flow velocity (TRV) occurs in approximately 30% of adults with sickle cell disease (SCD) and is reported to be an independent risk factor for early death with a mortality rate as high as 40% after 4 years. We previously presented the results on a cohort of 85 consecutive ambulatory sickle cell patients that were prospectively screened for elevated TRV (2.5 m/sec) using trans-thoracic echocardiography. We aimed to determine the mortality rate in relation to TRV and associated factors in a well characterized cohort of sickle cell disease patients in the Netherlands. Follow up consisted of regular outpatient visits including laboratory testing and repeated echocardiography every 2 years. Baseline hemoglobin (Hb), lactate dehydrogenase (LDH), brain natriuretic peptide (BNP), N-terminal pro brain natriuretic peptide (NT-proBNP), asymmetric dimethylarginine (ADMA) and arginine plasma levels were related to outcome, as were baseline pulmonary function tests and coagulation studies. The prevalence of elevated TRV in the cohort at baseline was 30% (41% in HbSS/HbS0-thalassemia patients and 13% in HbSC/HbS+-thalassemia patients). Median (IQR) follow-up for the whole group was 53 months (50-57). No patients were lost to follow-up. Four patients (3 HbSS and 1 HbSβ0-thalassemia) died during follow-up. Two of these patients had an elevated TRV at baseline while the other two initially had immeasurable TRV, resulting in a death rate for patients with an elevated TRV of 8% and a ratio for early death in of 2.3 (95 percent confidence interval, 0.3 to 16.6; p=0.40) However, the two patients with immeasurable TRV at baseline had an elevated TRV (2.55 m/sec and 2.92 m/sec) on repeated echocardiography two years later. Median age of the patients who died was 48 (34-58) years compared to 29 (21-44) years of those who survived (p=0.18). Baseline plasma levels (medians (IQR)) of Hb and LDH in the deceased were 4.7 (4.3-5.0) mmol/L and 676 (575-801) U/L compared to 5.4 (4.8-6.0) and 410 (341-629) in the survivors (p=0.075 and p=0.049) respectively. Baseline median NT-proBNP plasma levels in the deceased were 278 (131-686) pg/mL and 520 (154-3957) pg/mL compared to 45 (26-94) and 91 (52-150) in the survivors (p=0.007 and p=0.03) respectively. Pulmonary function testing, coagulation studies and plasma levels of ADMA and arginine were not associated with mortality in this cohort. Conceding the relative young age of our cohort, we conclude that the mortality in sickle cell patients with elevated TRV values was far lower as compared to the published literature. Although an elevated TRV could still be an important risk factor for early death, mortality may in fact be much lower than previously reported which is in line with more recent observations by other groups. With respect to biomarkers, we confirmed that NT-pro BNP and BNP levels were significantly higher in patients who died, with a trend toward a higher rate of hemolysis as well. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cumulative Incidences and Risk Factors for Intra and Extracranial Cerebral Arteriopathy in Sickle Cell Disease Children

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 56-57
Author(s):  
Francoise Bernaudin ◽  
Suzanne Verlhac ◽  
Cécile Arnaud ◽  
Annie Kamdem ◽  
Isabelle Hau ◽  
...  
Keyword(s):  
Risk Factors ◽  
At Risk ◽  
Risk Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cumulative Incidence ◽  
Intracranial Stenosis ◽  
Cell Disease ◽  
Independent Risk Factors

In children with sickle cell disease (SCD), cerebral vasculopathy is responsible for overt strokes and silent cerebral infarcts (SCI). Transcranial Doppler (TCD) detects children at risk of strokes (intracranial time averaged mean of velocities (TAMV) ≥200cm/s). The extracranial portion of the internal carotid artery (eICA) can also be the site of stenosis or occlusion. eICA assessment requires cervical Doppler using a submandibular approach and cervical MRA (cMRA). We previously reported that eICA TAMV≥160cm/s are highly predictive of eICA stenosis and are a risk factor for SCI independently of acute and chronic anemia. However, the kinetics of eICA arteriopathy are unknown. The aim here was to evaluate and compare the cumulative incidence of intra/extracranial arteriopathy and associated risk factors in a longitudinal SCD cohort. Children born between 01/1988 and 01/ 2018, followed at our center at least until 06/2012 and up to 09/2019, annually assessed by TCD imaging and at least once by cervical Doppler were included, resulting in 493 SCD children (238F-255M) with 398 SCA (385SS,10Sb0,3SDPunjab), and 95 SC/Sb+ children (65SC,30Sb+). Alpha-genes, b-globin haplotypes, G6PD activity, CD36 expression were recorded. The average of baseline biologic parameters recorded between 1 and 3 years of age, a minimum of 3 months away from transfusion, 1 month from a painful episode, and before any intensive therapy was calculated. The median (range) follow-up of the overall cohort was 10.6 years (1.1-22.9), providing 5335 patient-years of follow-up. Six deaths occurred (5 SCA-children at 2, 4, 7, 19 & 20 years and 1 in SB+ patient at 13 years). Three SS patients had an ischemic stroke at 1.5, 3 and 4.3 years. Kaplan-Meier estimates of cumulative incidence (95%CI) are shown (Figure). In SCA-children, abnormal eICA TAMV and/or eICA stenosis were sometimes associated with abnormal intracranial TAMV and/or stenosis, but isolated eICA TAMV≥200cm/s or 160-199cm/s were observed in 19 (4.8%) and 28/398 (7.0%) patients, respectively, and isolated eICA stenoses in 33/294 (11.2%).Thus, risk factors were only analyzed in patients with isolated intra- or extracranial arteriopathy. COX regression analyses are shown (Table). For isolated intracranial TAMV≥200cm/s, multivariate analyses after introducing all significant genetic and biological risk factors retained the number of SEN b-haplotypes [HR=0.547 (95%CI:0.335-0.893); p=0.016], reticulocyte count>400x109/L [HR=1.961 (95%CI:1.119-3.436); p=0.019], and WBC count>20x109/L [HR=2.410 (95%CI:1.340-4.329); p=0.003] as independent risk factors. Isolated eICA TAMV≥160 cm/s were only strongly associated with the presence of tortuosities [HR=8.6 (95%CI :4.3-17.2); p<0.001]. eICA tortuosities were present in 94/284 (33.1%) SCA vs 5/43 (11.6%) SC/Sb+ children (p=0.004), most often seen at the first cMRA but secondarily in 16 patients. Multivariate COX analysis retained genotype [HR/SCA vs SC/Sb+ = 3.6 (95%CI:1.4-9.4); p=0.010], low hemoglobin [HR=1.25 (95%CI:1.04-1.50); p=0.020], and high LDH [HR=1.002 (95%CI:1.001-1.002); p=0.001], as independent risk factors for eICA tortuosities. As expected, the risk of intracranial stenosis was significantly associated with isolated intracranial TAMV≥200 cm/s [HR (95%CI)=4 .255 (2.146-8.475); p<0.001]. After adjustment with isolated intracranial TAMV≥200 cm/s, a-thalassemia, low hemoglobin, high WBC, MCV and LDH remained as significant, but not independent, risk factors for intracranial stenosis. The risk for eICA stenosis was only highly associated with the presence of tortuosities [HR=10.9 (95%CI:4.7-25.0); p<0.001], or a history of eICA≥160cm/s [HR=15.4 (95%CI :7.5-31.2); p<0.001]. This study reports eICA arteriopathy kinetics using a longitudinal cohort of SCD children systematically assessed by Doppler and cMRA. While we confirm that only SCA and not SC/Sb+ children are at risk of intra/extracranial arteriopathy, we show for the first time that extracranial arteriopathy progressively develops as early as 2 years old in SCA-children and reaches a plateau around 10 years of age, as for intracranial arteriopathy. Furthermore, eICA tortuosities, which are the risk factor for eICA arteriopathy, are themselves significantly and independently associated with the SCA genotype and the severity of hemolytic anemia. Figure Disclosures Bernaudin: BlueBirdBio: Consultancy; AddMedica: Honoraria, Other; GBT: Membership on an entity's Board of Directors or advisory committees. Verlhac:BlueBirdBio: Consultancy; AddMedica: Honoraria.

Usual Clinical Parameters Underestimate the Incidence and Significance of Erythropoietin Deficiency as a Risk Factor for Death in Sickle Cell Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3791-3791
Author(s):  
Santosh Saraf ◽  
Seema Sidhwani ◽  
Mohammed Farooqui ◽  
Stephen Vara ◽  
Joseph DeSimone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Early Death ◽  
Organ Damage ◽  
Endocrine Function ◽  
Clinical Parameters ◽  
Cell Disease ◽  
Epo Deficiency

Abstract A robust reticulocytosis is necessary to maintain hemoglobin levels compatible with life in patients with sickle cell disease. Relative reticulocytopenia, defined as a absolute reticulocyte count less than 250 x 109/L despite hemoglobin <9g/dl, has been identified as a risk factor for early death. RR could result from chronic bone marrow vaso-occlusive insult or a renal endocrine defect leading to erythropoietin (EPO) deficiency. In non-SCD patients, EPO levels and creatinine clearance are clinical parameters that are used to define patients with anemia from EPO deficiency. The normal ranges for these parameters may not apply to SCD, and therefore the incidence and significance of EPO deficiency in SCD may have been underestimated, compromising rational EPO replacement therapy. In a retrospective analysis of 417 patients with HbSS or S-β-thalassemia, confirming previous findings, RR was a risk factor for early death. There was a significant association between RR and proteinuria. Usually, there is an inverse correlation between hemoglobin and EPO levels (negative feed-back), this was seen in patients without RR. However, in patients with proteinuria, the correlation between hemoglobin and EPO levels was a positive one, suggesting hemoglobin dependence on EPO levels. Proteinuria or increased creatinine levels were a risk factor for early death but not if RR was included in the model, suggesting the increased risk of death associated with proteinuria and creatinine was mediated by RR. RR was also associated with decreased platelet and WBC counts, suggesting a contribution by cumulative vaso-occlusive bone marrow damage to RR. However, platelet and WBC counts were not risk factors for early death within the cohort. Damage to renal endocrine function/EPO deficiency should be added to the list of clinically significant chronic organ damage in SCD. EPO deficiency may precede and be causative of other end-organ damage, such as cardiac diastolic dysfunction and renal exocrine failure. Proteinuria should be recognized as a clinical parameter that should prompt consideration of EPO deficiency. Since EPO replacement is clinically feasible, renal endocrine dysfunctiton is a cause of symptoms, clinical deterioration and death that could be rationally addressed.

Pulmonary Hypertension in Sickle Cell Disease: Correlation With Echocardiographic Assessment and Serum Brain Natriuretic Peptide Concentration

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4680-4680
Author(s):  
Salam Alkindi ◽  
Zeba Jabeen ◽  
Anil Pathare ◽  
Mohammed Al-Huneini ◽  
Murtadha Al Khabori ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sickle Cell ◽  
Pulmonary Function Tests ◽  
Direct Bilirubin ◽  
Cell Disease ◽  
Function Tests

Background & Purpose Pulmonary hypertension (PH) in sickle cell disease (SCD) is an important risk factor for complications including sudden death. In this study, we aimed to determine the prevalence of PH and correlate the echocardiographic parameters and general laboratory data with markers of hemolysis and serum NT pro-brain natriuretic peptide [BNP] concentrations in Omani SCD patients. Methods A cohort of 163 SCD patients [Mean age 25.4±8.4 years], in steady state was prospectively screened for PH with Doppler echocardiography (defined as a tricuspid regurgitation jet flow velocity of ≥ 2.5 m/sec and/or mean pulmonary artery pressure [mPAP] ≥25 mmHg). After a written informed consent, all patients were investigated with a complete blood count, renal chemistry, hemolytic parameters including LDH, haptoglobin, liver function tests, coagulation studies, HPLC studies including HbS and HbF level estimations, X ray Chest, ECG, ABG, Pulmonary function tests, Pulse oximetry, and Serum NT pro-BNP levels. Results In the evaluable patient cohort of 116 subjects [63 females, 53-males], the prevalence of PH was 5.2%. No statistically significant differences were detected in Hb levels, ECG, chest radiography, pulmonary function tests between patients with and without PH. However, plasma NT pro-BNP levels were significantly correlated with PAH [r=0.934, p<0.000], TRV jet [r=.671, p<0.000], Abnormal ECHO [r=0.672, p<0.000], and direct Bilirubin levels [r=0.278,p<0.009] in SCD patients. Furthermore, in SCD patients with PH, there was a statistically significant increase in plasma NT pro-BNP levels [ p<0.001], ALT [p<0.02], S. Creatinine [p=0.045] and Total bilirubin [p<0.0001] and direct Bilirubin levels [p<0.0001][Table]. Conclusions Serum NT pro-BNP is a strong indicator of PH in SCD patients. Doppler ultrasound echocardiography is a useful initial screen for PH in SCD patients. The correlation between PH and hemolytic markers suggests an implication in the pathogenesis of PH. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for Sickle Cell Disease: Updated Results of the Multicenter Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 104-104 ◽  
Author(s):  
Mark C. Walters ◽  
Melinda Patience ◽  
Sandie Edwards ◽  
Shanda Robertson ◽  
Marsha McMurray ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Sickle Cell ◽  
Graft Versus Host Disease ◽  
Graft Rejection ◽  
Gonadal Function ◽  
Cell Disease ◽  
Graft Versus Host ◽  
History Of

Abstract Between 1991 and 2000, 59 children with symptomatic sickle cell disease (SCD) were enrolled in a multicenter investigation of myeloablative HLA-identical sibling bone marrow transplantation (BMT). Patients had stroke (N=30) or other significant central nervous system disease (CNS) (N=1), recurrent episodes of acute chest syndrome (ACS) (N=20), or recurrent painful episodes (N=8) before study entry. Currently, 55 patients survive, and 50 survive free of sickle cell disease. Four patients died of complications of graft-versus-host disease (GVHD)(N=3) or intracranial hemorrhage (N=1). Five patients had graft rejection accompanied by return of SCD. With a median follow-up of 5.2 years, the Kaplan-Meier probabilities of survival and event-free survival are 93% and 85%, respectively. To investigate the toxicity of transplantation and to assess its impact on the natural history of SCD, long-term follow-up evaluations of the CNS, pulmonary function, and gonadal function were performed. As reported previously, engrafted patients with stroke had no subsequent stroke events after BMT, and cerebral MRI and MRA exams demonstrated stable or improved appearance. One patient with graft rejection experienced a second stroke when the Hb S fraction reached 60% after BMT. Forty-three of 55 surviving (78%) patients had pulmonary function testing (PFT) performed at least 1 year after BMT, and 24 were tested 3 or more years after BMT. Seven of the 12 who lacked follow-up testing had normal baseline testing. Of the 43 with follow-up exams, 30 had stable, and 8 had improved PFTs. Five had worsened pulmonary function, 4 with restrictive changes, and 1 with obstructive changes. Three of the 4 with progression of restrictive changes had a history of ACS before BMT. One patient with a history of ACS died of pulmonary complications caused by graft-versus-host disease. Currently, 24 males and 19 females treated by BMT are >14 years of age. Of these, 15 males (63%) and 14 (74%) females had post-BMT gonadal function studies performed. Eleven of 15 males had normal LH and FSH levels, however, a normal testosterone level was observed only in 4. In contrast, 9 of 14 females had elevated gonadotropin and decreased estradiol levels that mimicked a post-menopausal state. Six females had primary or secondary amenorrhea. In summary, patients with stable engraftment of donor cells had cessation of clinical complications of SCD after BMT. In addition, most had stabilization or improvement in sub-clinical markers of disease. However, a limited number of patients who had progression of PFT abnormalities also had a history of ACS before BMT. In addition, gonadal toxicity was observed commonly in females after BMT. Together, these data confirm that BMT is a suitable intervention for patients with severe sickle cell disease, however efforts to reduce the toxicity of BMT should be pursued.

Hospital Readmission within 30 Days: A New Benchmark for Quality Care among Children with Sickle Cell Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3403-3403
Author(s):  
Melissa J. Frei-Jones ◽  
Michael R. DeBaun
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Quality Of Care ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hospital Readmission ◽  
Cell Disease ◽  
First Admission

Abstract The National Association of Children’s Hospitals and Related Institutions (NACHRI) has established benchmarks for measuring quality of care in children that are hospitalized. Readmission within 30 days of discharge is the benchmark chosen to assess the quality of care for patients with Sickle Cell Disease (SCD). Limited data exist to determine risk factors for re-admission and whether such risk factors are modifiable. We performed a retrospective case-control study to identify risk factors for hospital readmission in children with SCD. All hospital admissions of patients with SCD for one year were reviewed. Cases were defined as children with SCD who were readmitted within 30 days of their first admission during the 12 month study period. Controls were defined as children with SCD who were not readmitted within 30 days of their first admission. A total of 30 cases and 70 controls were identified. The average time between admissions was 10.7 days with 50% readmitted within 8 days and 77% readmitted within 21 days. No difference in demographic data was found between cases and controls. The most common admission and readmission diagnosis was pain, 78% and 70%, respectively. The greatest risk factor for readmission was no follow-up appointment within 30 days after discharge in the SCD clinic (OR 7.7, 95% CI 2.4–24.4). The second highest risk factor was severity of disease, defined as patients with ≥ 3 hospitalizations in the previous 12 months versus patients with ≤ 2 hospitalizations in the previous 12 months (OR 7.3, 95% CI 2.8–18.9). A diagnosis of asthma was also a risk factor for readmission (OR 2.9, 95% CI 1.2–7.3). Patients who initially required supplemental oxygen to maintain their oxygen saturation in the normal range and were subsequently on room air for ≤ 24 hours at discharge were also more likely to be readmitted (OR 3.3, 95% CI 1.1–9.7). Steroid administration was not a risk factor for readmission (OR 1.2, 95% CT 0.5–3.2). Potential modifiable risk factors exist to decrease the rate of readmission. Specifically, strategies targeted at the modification of disease severity, aggressive management of asthma, and outpatient follow-up after hospitalization may decrease the 30 day readmission rate.

scholarly journals Variability of Prognostic Results Based on Biological Parameters in Sickle Cell Disease Cohort Studies in Children: What Should Clinicians Know?

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 143
Author(s):  
Julie Sommet ◽  
Enora Le Roux ◽  
Bérengère Koehl ◽  
Zinedine Haouari ◽  
Damir Mohamed ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Sickle Cell Disease ◽  
Cohort Studies ◽  
Statistical Methods ◽  
Sickle Cell ◽  
Biological Parameters ◽  
Analysis Method ◽  
Cell Disease ◽  
Statistical Analysis Method

Background: Many pediatric studies describe the association between biological parameters (BP) and severity of sickle cell disease (SCD) using different methods to collect or to analyze BP. This article assesses the methods used for collection and subsequent statistical analysis of BP, and how these impact prognostic results in SCD children cohort studies. Methods: Firstly, we identified the collection and statistical methods used in published SCD cohort studies. Secondly, these methods were applied to our cohort of 375 SCD children, to evaluate the association of BP with cerebral vasculopathy (CV). Results: In 16 cohort studies, BP were collected either once or several times during follow-up. The identified methods in the statistical analysis were: (1) one baseline value per patient (2) last known value; (3) mean of all values; (4) modelling of all values in a two-stage approach. Applying these four different statistical methods to our cohort, the results and interpretation of the association between BP and CV were different depending on the method used. Conclusion: The BP prognostic value depends on the chosen statistical analysis method. Appropriate statistical analyses of prognostic factors in cohort studies should be considered and should enable valuable and reproducible conclusions.

scholarly journals Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 5010-5020 ◽  
Author(s):  
Kori L. Wallace ◽  
Joel Linden
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Nk Cells ◽  
Natural Killer ◽  
Sickle Cell ◽  
Pulmonary Injury ◽  
Cell Disease ◽  
Inkt Cells ◽  
Adenosine A2a ◽  
Hypoxia Reoxygenation

Abstract We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A2A receptor (A2AR) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A2AR agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1−/− mice reduced pulmonary injury that was restored by adoptive transfer of 106 purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A2AR alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ϵ]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A2ARs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation–induced exacerbation of pulmonary injury. A2A agonists have promise for treating diseases associated with iNKT or NK cell activation.

scholarly journals Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 636-646 ◽  
Author(s):  
Pichika Chantrathammachart ◽  
Nigel Mackman ◽  
Erica Sparkenbaugh ◽  
Jian-Guo Wang ◽  
Leslie V. Parise ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Sickle Cell Disease ◽  
Tissue Factor ◽  
Sickle Cell ◽  
Plasma Levels ◽  
Cell Injury ◽  
Vascular Inflammation ◽  
Cell Disease ◽  
Endothelial Cell Injury ◽  
Cell Adhesion Molecule 1

Abstract Sickle cell disease (SCD) is associated with a complex vascular pathophysiology that includes activation of coagulation and inflammation. However, the crosstalk between these 2 systems in SCD has not been investigated. Here, we examined the role of tissue factor (TF) in the activation of coagulation and inflammation in 2 different mouse models of SCD (BERK and Townes). Leukocytes isolated from BERK mice expressed TF protein and had increased TF activity compared with control mice. We found that an inhibitory anti-TF antibody abrogated the activation of coagulation but had no effect on hemolysis or anemia. Importantly, inhibition of TF also attenuated inflammation and endothelial cell injury as demonstrated by reduced plasma levels of IL-6, serum amyloid P, and soluble vascular cell adhesion molecule-1. In addition, we found decreased levels of the chemokines MCP-1 and KC, as well as myeloperoxidase in the lungs of sickle cell mice treated with the anti-TF antibody. Finally, we found that endothelial cell-specific deletion of TF had no effect on coagulation but selectively attenuated plasma levels of IL-6. Our data indicate that different cellular sources of TF contribute to activation of coagulation, vascular inflammation, and endothelial cell injury. Furthermore, it appears that TF contributes to these processes without affecting intravascular hemolysis.

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