scholarly journals Sickle Cell Disease: A Paradigm for Venous Thrombosis Pathophysiology

2020 ◽  
Vol 21 (15) ◽  
pp. 5279
Author(s):  
Maria A. Lizarralde-Iragorri ◽  
Arun S. Shet
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Venous Thrombosis ◽  
Mouse Models ◽  
Sickle Cell ◽  
Venous Stasis ◽  
Cell Disease ◽  
Cellular Mechanisms ◽  
Blood Clots ◽  
Venous Vasculature

Venous thromboembolism (VTE) is an important cause of vascular morbidity and mortality. Many risk factors have been identified for venous thrombosis that lead to alterations in blood flow, activate the vascular endothelium, and increase the propensity for blood coagulation. However, the precise molecular and cellular mechanisms that cause blood clots in the venous vasculature have not been fully elucidated. Patients with sickle cell disease (SCD) demonstrate all the risk factors for venous stasis, activated endothelium, and blood hypercoagulability, making them particularly vulnerable to VTE. In this review, we will discuss how mouse models have elucidated the complex vascular pathobiology of SCD. We review the dysregulated pathways of inflammation and coagulation in SCD and how the resultant hypercoagulable state can potentiate thrombosis through down-regulation of vascular anticoagulants. Studies of VTE pathogenesis using SCD mouse models may provide insight into the intersection between the cellular and molecular processes involving inflammation and coagulation and help to identify novel mechanistic pathways.

scholarly journals Thromboembolic Complications in Patients with Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4913-4913
Author(s):  
Salam Alkindi ◽  
Anwaar Al-Ghadani ◽  
Samah Al-zeheimi ◽  
Anil Pathare
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Venous Thrombosis ◽  
Sickle Cell ◽  
Significant Risk ◽  
Central Venous Catheters ◽  
Morbidity And Mortality ◽  
Thromboembolic Complications ◽  
Cell Disease ◽  
Central Venous

Abstract Background and Purpose: Venous thromboembolism (VTE) is common in patients with sickle cell disease (SCD). Traditional risk factors such as central venous catheters, frequent hospitalization, orthopedic surgeries for avascular necrosis, and pregnancy often leads to an increased incidence of VTE in the SCD. In addition, SCD itself appears to be a hypercoagulable state with many SCD-specific factors such as genotype, splenectomy and thrombophilia modifying the risk of VTE. This study aims to assess the clinical and pathological characteristics of VTE amongst a cohort of patients with SCD at the Sultan Qaboos University Hospital and determine its relation to morbidity and mortality. Methodology: In this retrospective case control study, medical details of all patients with SCD who developed thromboembolic complications over the past decade were retrieved from the hospital information system. SCD patients matched for age and gender (2:1 ratio) who did not have thromboembolic complications but had a thrombophilia screen performed served as controls. The study was approved by the local Medical Research and Ethics Committee. Results & Discussion: A total of 53 SCD patients were enrolled [34 cases, 19 controls] in this study. Amongst the 34 cases (mean age-30 yrs.), 18 had pulmonary embolism, eight had deep venous thrombosis, whereas, three each had cerebral venous thrombosis and portal venous thrombosis and one each had cerebral arterial thrombosis and VTE. A higher incidence of autosplenectomy(69.7% v/s 52.6%) and central venous catheters(42.4% v/s 5.3%) were significantly associated with thrombosis (p<0.05, Chi Square test). High LDH levels, WBC and Platelet counts were significant risk factors(p<0.05) for VTE. 21 patients [63.6%] amongst the cases developed acute chest syndrome, where 3[9%] had cerebrovascular accident. Mortality was seen in seven cases [21%]. Conclusions: The study shows that thromboembolic complications in SCD has a high impact on the morbidity and mortality. It confirms PE as the leading cause for VTE in SCD with asplenia, central venous catheter, high LDH, WBC and Platelet counts being significant risk factors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Neuropathic Pain in Children with Sickle Cell Disease: The Hidden Side of the Vaso-Occlusive Crisis

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 84
Author(s):  
Jeanne Sigalla ◽  
Nathalie Duparc Alegria ◽  
Enora Le Roux ◽  
Artemis Toumazi ◽  
Anne-Françoise Thiollier ◽  
...  
Keyword(s):  
Risk Factors ◽  
Neuropathic Pain ◽  
Sickle Cell Disease ◽  
Sex Ratio ◽  
Prospective Study ◽  
Sickle Cell ◽  
Clinical Presentation ◽  
Early Stage ◽  
Cell Disease ◽  
A Prospective Study

The majority of hospitalizations of patients with sickle cell disease (SCD) are related to painful vaso-occlusive crises (VOCs). Although the pain of VOC is classically nociceptive, neuropathic pain (NP) has also been demonstrated in SCD patients. The aim of our study is to specify the prevalence of NP during VOCs in SCD children using a dedicated scale and to measure its characteristics. We performed a prospective study that included SCD children hospitalized for an acute VOC. The presence of NP was sought with the DN4 scale on the second and fourth days of hospitalization. A total of 54 SCD children were included in the study. Overall, 41% of the patients (n = 22) experienced neuropathic pain during the VOC, mostly at an early stage (Day 2). The median age, the sex ratio, the location of the pain, and the morphine consumption were similar for patients with and without NP. Our study shows that neuropathic pain is very common during VOCs in SCD children. The absence of identified risk factors should prompt us to be vigilant regardless of the patient’s age, sex, and clinical presentation.

scholarly journals Engineering, Generation and Preliminary Characterization of a Humanized Porcine Sickle Cell Disease Animal Model

2020 ◽  
Author(s):  
Tobias M. Franks ◽  
Sharie J. Haugabook ◽  
Elizabeth A. Ottinger ◽  
Meghan S. Vermillion ◽  
Kevin M. Pawlik ◽  
...  
Keyword(s):  
Animal Model ◽  
Sickle Cell Disease ◽  
Mouse Models ◽  
Sickle Cell ◽  
Cell Model ◽  
Globin Genes ◽  
Cell Disease ◽  
Small Vessels

AbstractMouse models of sickle cell disease (SCD) that faithfully switch from fetal to adult hemoglobin (Hb) have been important research tools that accelerated advancement towards treatments and cures for SCD. Red blood cells (RBCs) in these animals sickled in vivo, occluded small vessels in many organs and resulted in severe anemia like in human patients. SCD mouse models have been valuable in advancing clinical translation of some therapeutics and providing a better understanding of the pathophysiology of SCD. However, mouse models vary greatly from humans in their anatomy and physiology and therefore have limited application for certain translational efforts to transition from the bench to bedside. These differences create the need for a higher order animal model to continue the advancement of efforts in not only understanding relevant underlying pathophysiology, but also the translational aspects necessary for the development of better therapeutics to treat or cure SCD. Here we describe the development of a humanized porcine sickle cell model that like the SCD mice, expresses human ɑ-, β− and γ-globin genes under the control of the respective endogenous porcine locus control regions (LCR). We also describe our initial characterization of the SCD pigs and plans to make this model available to the broader research community.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value &lt; 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Alkaline Phosphatase Is Associated with Red Cell Alloimmunization in the Pulmonary Hypertension and Hypoxic Response (PUSH) Sickle Cell Disease Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Victoria Brooks ◽  
Oluwalonimi Adebowale ◽  
Victor R. Gordeuk ◽  
Sergei Nekhai ◽  
James G. Taylor
Keyword(s):  
Risk Factors ◽  
Alkaline Phosphatase ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Severe Disease ◽  
Case Control ◽  
Red Cell ◽  
Cell Disease ◽  
History Of

Background: Blood transfusion is a common therapy for sickle cell disease (SCD). Although, highly effective, a major limitation is development of alloantibodies to minor blood group antigens on donor red cells. Alloimmunization has a prevalence of 2-5% for transfusions in the general population, but it is significantly higher in SCD. Risk factors for alloimmunization have been poorly characterized, although number of lifetime transfusions is an important risk factor. Alloimmunization has been clinically observed in children with a prevalence of about 7%. With development of each antibody, blood donor matching becomes increasingly difficult and expensive with an increased risk for transfusion reactions and diminished availability of compatible red cell units for treatment of SCD. The ability to identify risk factors for developing alloantibodies would be beneficial for clinicians. To identify markers for alloimmunization in SCD, we have analyzed children and adults who developed this complication. Methods: We analyzed The Pulmonary Hypertension and Hypoxic Response in Sickle Cell Disease (PUSH) study, which enrolled n=468 pediatric and n=59 adult SCD subjects. In both children and adults, alloimmunization cases were defined as a history of at least 1 alloantibody. Controls in both cohorts were defined as subjects with no history of alloantibodies and receipt of more than 10 lifetime red cell transfusions. All others within the study who did not meet these criteria were assigned to a third comparison group. To identify differences between cases, controls and all others, we performed univariate analyses (using ANOVA or Kruskal Wallace where appropriate) for clinical parameters and laboratories. Case control comparisons were also performed for selected variables and plasma levels for 11 cytokines. Results were further analyzed using regression modeling. Results: The overall prevalence of alloimmunization was 7.3% among children (34/468 subjects; median age 12, range 3-20 years) compared to 28.8% in adults (17/59 subjects; median age 37, range 18-73 years). When only considering those with &gt;10 lifetime transfusions, the prevalence was considerably higher at 29.3% and 54.8% in children and adults, respectively. At the same time, 8 pediatric (23.5%) and 5 adult (29.4%) alloimmunization cases had received fewer than 10 transfusions. In a 3-way pediatric cohort comparison (cases, controls and all others), risk factors associated with alloimmunization included SS genotype, older age and markers of more severe disease (higher ferritin, WBCs, platelets and total bilirubin). Comparison of cases to controls showed alkaline phosphatase (P=0.05) was significantly lower in cases, whereas AST (P=0.02) was significantly higher even with adjustment for age. Levels of plasma cytokines MCP-1 (P=0.01) and IFNgamma (P=0.08) were lower in cases from a subset of the pediatric cohort. In adults, only 4/59 (6.8%) subjects had never received a lifetime transfusion (all non-SS). In the adult 3-way comparisons, only SS genotype and higher ferritin were associated with alloimmunization. The adult case control analysis showed higher absolute monocyte count (P=0.02), absolute eosinophil count (P=0.04) and absolute basophil count (P=0.008) in association with alloimmunization cases. In addition, alkaline phosphatase was again significantly lower among cases (P=0.02) as seen in the pediatric cohort. There were no significant differences in cytokine levels among adults. Conclusions: When considering only transfused SCD patients, the prevalence of alloimmunization is higher than 30%. As seen in prior studies, higher lifetime red cell transfusions are an important risk factor especially among adults where most patients have received transfusions. Children who develop alloantibodies appear to have laboratory markers of more severe disease, but this is not observed in adults. A novel association observed across both pediatric and adult subjects is a significantly lower serum alkaline phosphatase in those with alloantibodies. The results of this study suggest a need for improved tracking of red cell transfusion therapy in the US for SCD patients due to a high prevalence of alloimmunization. Further study is also needed to elucidate the significance of the alkaline phosphatase association. Disclosures Gordeuk: CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding.

scholarly journals Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 528-537 ◽  
Author(s):  
Karina Yazdanbakhsh ◽  
Russell E. Ware ◽  
France Noizat-Pirenne
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Blood Cell ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Cell Disease ◽  
Factors Associated ◽  
Life Threatening ◽  
Red Blood Cell Transfusions ◽  
Transfusion Reactions

Abstract Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication.

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