Clinical relevance of vascular endothelial growth factor levels in sickle cell disease

In recent years, vascular inflammation, marked by activated monocytes and endothelium, has been proven to play a significant role in the pathogenesis of vaso-occlusive events (VOEs) in sickle cell disease (SCD). Vascular endothelial growth factor (VEGF), an endothelial cell mitogen, has been shown to contribute to the increased endothelial cell adhesivity by increasing the expression of cell adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) on the endothelium. We have investigated VEGF alterations in 37 patients with SCD during VOEs and/or steady state. VEGF levels (mean±SEM) were found to be significantly elevated during VOEs (703.1±119.0 pg/ml) when compared with those at steady state (258.0±57.8 pg/ml) and healthy controls (196.6±21.9 pg/ml) (p<0.001). However, we did not find a difference between VEGF concentrations in sickle patients at steady state and the normal subjects (p>0.05). We suggest that considering a possible stimulatory role of tissue hypoxia in VEGF production during VOEs, VEGF levels in sickle patients might be helpful in monitoring disease severity.     

Plasma PTX3 levels in sickle cell disease patients,during vaso occlusion and acute chest syndrome (data from Saudi population)

Background

Sickle cell disease (SCD) is a chronic, incurable hereditary disease. The vaso-occlusive crisis (VOC) is the most frequently occurring acute complication in sickle cell patients and accounts for the majority of SCD-related hospital admissions. Another major complication is the potentially fatal acute chest syndrome (ACS). The prototypic long pentraxin-3 (PTX3), an acute phase protein and a key component of innate immunity, is linked to ischemia-induced inflammation, a condition incriminated in SCD complications.

Aim

To investigate the expression of PTX3 in stable SCD and VOC patients and to assess its relation to the development and progression of ACS.

Subjects and methods

We conducted this study on 160 patients with confirmed SCD (20 stable SCD and 140 in VOC), and 10 healthy age- and sex-matched controls. Patients were diagnosed as SCD by high-performance liquid chromatography. PTX3 levels were assessed using enzyme-linked immunosorbant assay.

Results

In the stable state, all 20 SCD patients had PTX3 levels (range = 0.9–2.1 ng/ml; median = 1.1) comparable to those of healthy controls (range = 0.8–2.0 ng/ml; median = 1.0) (P > 0.05). During the VOC, plasma PTX3 significantly increased (range = 8.7–37.2 ng/ml; median = 22.3) (P < 0.01). Out of 140 VOC patients, 15 (10.7%) developed ACS and four required mechanical ventilation, of which two died. The median plasma level of PTX3 (22.3 ng/ml) was set as a cut-off value to stratify patients into low- and high-PTX3 expressers. Of the 140 VOC patients, 43 (30.7%) had PTX3 levels >22.3 ng/ml, of these, 13 patients developed ACS (13/43; 30.2%); of the remaining 97 patients who had PTX3 ≤22.3 ng/ml, only two patients (2/97; 2.1%) progressed to ACS, with a further increment in PTX3 in all of them. PTX3 levels were correlated with length of hospital stay in VOC patients and markers of lung injury in ACS patients.

Conclusion

PTX3 levels were higher in SCD patients in VOC, being associated with longer hospital stay. Higher initial PTX3 concentrations were related to the development of ACS with a further increase in PTX3 levels observed upon progression to ACS. Thus, PTX3 could be used as a subjective method to predict occurrence and severity of SCD acute complications.     

Platelet distribution width (PDW) is increased in vaso-occlusive crisis in sickle cell disease

Considering the multigenic and multifactorial nature of the disease, we argue that a generalized bone marrow hyperplasia—and not merely erythroid hyperplasia—will occur in sickle cell disease. Consequently, we expect the hematological parameters to depict erythroid, myeloid as well as megakaryocyte hyperplasia. In the light of this expectation, we hypothesized that platelet distribution width (PDW) will increase in sickle cell disease. Here, we report the results from a cross-sectional study of 216 children admitted with complaints suggestive of vaso-occlusive crisis. We observed a strong association between PDW and sickle cell disease as compared to children who had HbAA genotype. Our findings bridge previous inconsistencies relating to the role of platelets in sickle cell disease. Implications of this finding are discussed.     

Relation between glutathione S-transferase genes (GSTM1, GSTT1, and GSTP1) polymorphisms and clinical manifestations of sickle cell disease in Egyptian patients

Abstract

Objectives

Clinical manifestations of sickle cell disease (SCD) result from sickling of Hb S due to oxidation, which is augmented by accumulation of oxygen-free radicals. Deficiencies in normal antioxidant protective mechanism might lead to clinical manifestations of SCD like vaso-occlusive crisis (VOC) and acute chest syndrome (ACS). The glutathione system plays an important role in the removal of endogenous products of peroxidation of lipids, thus protecting cells and tissue against damage from oxidative stress. Impairment of the glutathione system due to genetic polymorphisms of glutathione S-transferase (GST) genes is expected to increase the severity of SCD manifestations. This report describes a case control study aimed at studying the ethnic-dependent variation in the frequency of GST gene polymorphisms among participants selected from the Egyptian population and to find out the association between GST gene polymorphisms and the severity of SCD manifestations.

Methods

We measured the frequency distribution of the three GSTs gene polymorphisms in 100 Egyptian adult SCD patients and 80 corresponding controls. GSTM1 and GSTT1 genotypes were determined by multiplex polymerase chain reaction (PCR). GSTP1 genotyping was conducted with a PCR-restriction fragment length polymorphism assay.

Results

The GSTM1 null genotype was significantly associated with ACS and VOC (P = 0.03 and 0.01, respectively). The GSTT1 null genotype was associated with significantly increased requirement of blood transfusion (P = 0.01). Absence of both GSTM1 and GSTT1 genes was significantly associated with pulmonary hypertension (P = 0.04). The non-wild-type GSTP1 polymorphism was not associated with clinical manifestations of SCD.

Discussion

Some GST gene polymorphisms were significantly associated with the worsening of the clinical manifestations of SCD.     

Red cell exchange in sickle cell disease

Red cell exchange transfusion is frequently of use in the management of patients with sickle cell disease either electively or therapeutically. Modern cell separators allow this procedure to be performed rapidly, effectively and safely. These machines have a number of advantages over manual exchange procedures. The patient remains isovolaemic, there is little loss of plasma or platelets, the procedure is relatively short and in elective circumstances can be performed on an outpatient basis. In this series 66 exchanges were performed on 21 patients with an overall increase in HbA of 70%. The COBE Spectra gave a mean increase in HbA of 77%, with the majority of patients achieving an HbA of > 90% post exchange. Automated redcell exchange was well tolerated by most patients, and adverse effects were limited to symptoms of hypocalcaemia which were easily treated, and to transfusion reactions. Cell separators can therefore be recommended for exchange transfusion in patients with sickle cell disease, who require an increase in HbA levels either prophylactically or therapeutically. They are safe, effective, easy and quick to use.     

The role of cytokines in sickle cell disease

Sickle cell disease (SCD) is characterized by chronic hemolysis, frequent infections, and recurrent occlusions of microcirculation, which cause painful crises and result in chronic organ damage and failure. Occlusions of the microcirculation and infections are important factors that stimulate the production of cytokines and acute-phase proteins. Cytokines seem to be involved with several possible mechanisms in the pathogenesis of vasoocclusive phenomena in SCD: vascular endothelial activation, induction of red-cell adhesiveness to vascular endothelium, induction of neutrophil adhesiveness to endothelium, development of vascular intimal hyperplasia, platelet activation, endothelin-1 production, and dysregulation of endothelial apoptosis. Cytokines are also thought to be involved in the regulation of hemopoiesis, the inhibition of immune functions, and the development of growth deficits. Investigation of cytokines in SCD patients will elucidate the pathogenesis of the disease and its complications and may help in assessing disease severity and prognosis. Received: 1 December 1999 / Accepted: 26 January 2000     

Systemic lupus erythematosus in patients with sickle cell disease

Sickle cell disease (SCD) is a prevalent genetic disorder that includes sickle cell anemia (hemoglobin SS), hemoglobin SC, and hemoglobin Sb-thalassemia. Patients with SCD present with a defective activation of the alternate pathway of the complement system that increases the risk of capsulate bacteria infection and failure to eliminate antigens, predisposing these patients to autoimmune diseases. The authors describe three patients with SCD that developed systemic lupus erythematosus (SLE). In all patients, SLE diagnosis was delayed because symptoms were initially attributable to SCD. Physicians should be alerted to the possible development of SLE in patients with SCD to not delay the diagnosis and start appropriate treatment.     

Cancer specific survival in patients with sickle cell disease

Sickle cell disease (SCD) patients have a higher incidence of certain cancers, but no studies have determined the impact of cancer on survival among SCD patients. SCD patients (n = 6423), identified from state-wide hospitalisation data, were linked to the California Cancer Registry (1988–2014). Multivariable Cox proportional hazards regression was used to examine survival. Among SCD patients, a cancer diagnosis was associated with a 3-fold increased hazard of death. Compared to matched cancer patients without SCD, SCD was associated with worse overall survival, but not cancer-specific survival, suggesting that SCD cancer patients should be treated with similar therapeutic intent.     

COVID-19 outcomes in sickle cell disease and sickle cell trait

Throughout the Coronavirus Disease 2019 (COVID-19) pandemic, understanding the effects of COVID-19 on persons with Sickle Cell Disease (SCD) and Sickle Cell Trait (SCT) has garnered interest. Patients with SCD diagnosed with COVID-19 utilize the emergency department and are hospitalized at significantly higher rates compared to the general population, with vaso-occlusive crisis and acute chest syndrome as the leading presentations. Whether SCD alone increases the likelihood of severe COVID-19 illness remains uncertain; however, potential risk factors for severe disease among patients with SCD include older age, frequent acute care visits for pain, haemoglobin SC disease, and pre-existing end-organ disease. SCT status may also influence COVID-19 outcomes, particularly among those with pre-existing co-morbidities. Corticosteroids in patients with SCD and COVID-19 should be used with extreme caution given strong associations between corticosteroid exposure and severe vaso-occlusive crisis, with prophylactic transfusion administered if corticosteroids are deemed necessary. Hydroxyurea may be protective in COVID-19.     

Atherosclerosis in sickle cell disease - a review

Acute, vaso-occlusive crises are the most common and earliest clinical manifestations of sickle cell disease. Recent thoughts about development of atherosclerosis as a result of this disease are presented. Current insights into the pathogenesis of atherosclerosis in sickle cell disease are reviewed, in particular the role of endothelial dysfunction, homocysteine and platelets. Common and uncommon sites of atherosclerosis are described. Radiological assessment and potential therapeutic agents to slow the progression of atherosclerosis are discussed. Finally, treatment of atherosclerosis in certain sites is evaluated and reviewed.     

Normal sublingual microcirculation during painful crisis in sickle cell disease

Obstruction of the microcirculation is the most important cause of painful crisis in sickle cell disease (SCD). Extensive microvascular obstruction has been observed in mouse models of SCD. A technique to determine the extent of the microcirculatory obstructions in humans may be helpful in the clinical setting and for research purposes. Therefore, we measured sublingual microcirculation longitudinally in patients with SCD admitted with painful crisis.Sublingual microcirculation was recorded with side-stream darkfield (SDF) imaging and semi-quantified with a microvascular flow index (MFI) on a range from 0 to 4 (arbitrary units; from 0 (no flow) to 4 (hyperdynamic flow)).Thirteen consecutive adult sickle cell patients admitted with painful crises were included and provided 47 measurements of MFI in 14 episodes of painful crisis. Seven patients provided baseline measurements and seven healthy controls were studied. The mean (± standard error of the mean) MFI during painful crisis was 2.6 ± 0.1 and did not change during the painful crisis. The mean MFI of patients with SCD during steady state (2.7 ± 0.1) and the mean MFI of the controls (2.7 ± 0.1) were not different from the mean MFI during painful crisis. During painful crisis irregular microvascular perfusion, expressed by the distribution width of the microvascular blood flow velocity, correlated negatively (r = − 0.484; P = 0.002) with hemoglobin concentration.We conclude that sublingual microcirculatory blood flow velocity is not disturbed in sickle cell patients during painful crisis.     

Surgical and obstetric outcomes in adults with sickle cell disease

Background

Sickle cell disease patients are more likely than the general population to undergo surgery and usually do so at a younger age. Female sickle cell disease patients also have special gynecological and obstetric issues related to their disease.

Methods

We collected data through standardized clinical report forms, patient interviews, and medical records from 509 adult sickle cell disease patients. Logistic regression was used to estimate the association between multiple variables and each of the surgery types. We also determined the prevalence and outcomes of pregnancy in 284 women with sickle cell disease in this population.

Results

Almost 50% of patients aged 18-27 years had had a cholecystectomy. Mean corpuscular hemoglobin, total bilirubin, and lactate dehydrogenase were significantly higher in the postcholecystectomy group; 9.5% of 504 individuals had undergone splenectomy. Hematocrit, body mass index, and red blood cell count were significantly higher in the postsplenectomy group. Hip replacement had been performed in 9.2% of individuals, with the prevalence increasing as early as the fourth decade and continuing to increase through the sixth decade of life. A history of pregnancy was present in 190 women (67%). Of 410 pregnancies, only 53.9% resulted in live births, 16.6% were voluntarily terminated, and 29.5% were complicated by miscarriage, still birth, or ectopic implantation.

Conclusions

Sickle cell disease continues to have a strong effect on the mean age for common surgeries and impacts pregnancy outcomes. We conclude that this population has a unique surgical and obstetric history that should be further studied to provide insight into potentially more effective preventive approaches to end-organ damage.     

Abnormalities of coagulation and fibrinolysis in homozygous sickle cell disease

Abnormalities of coagulation and fibrinolysis were studied in a group of 28 children and young adults with homozygous sickle cell disease (SCD), either in the steady state (n = 12) or during painful crisis (n = 16). Coagulation was explored by standard clotting tests and by measurement of prothrombin complex factors, factor VIII (VIII:C) and antithrombin III (ATIII), protein C (PC) and protein S (PS) activities, while fibrinolytic potential was evaluated using D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) assays. In SCD patients, thrombin time (TT) was constantly shortened, both in the steady state (ratio to control 0.83 ± 0.08, p < 0.0001) and in crisis (0.76 ± 0.06, p < 0.0001). Mean levels of prothrombin complex were similar in asymptomatic patients to those in controls, but were significantly decreased during sickle cell crisis (p < 0.05 for factor V and p < 0.0001 for factors II,VII and X). Factor VIII:C was significantly increased, both in the steady state (207 ± 35%, p < 0.0001) and during crisis (208 ± 34 %, p < 0,0001). PS activity was reduced in the steady state (81 ± 12%, p < 0.01) and further diminished in crisis (68.5 ± 27.5%, p < 0.001), while D-dimers were significantly elevated during sickle cell crisis (1028 ± 675 ng/ml, p < 0.001). In all SCD patients, baseline levels of t-PA antigen were comparable to those in controls, whereas concentrations of PAI-1 antigen were significantly increased, either in the steady state (89.7 ± 26.3 ng/ml, p < 0.0001) or in crisis (75.0 ± 24.8 ng/ml, p < 0.0001). These results provide evidence for the presence of circulating activated clotting factors in SCD and for an imbalance of the profibrinolytic and antifibrinolytic systems most likely due to increased PAI-1 levels.     

Standard management of sickle cell disease complications

Sickle cell disease remains a major public health concern in sub-Saharan Africa, Europe, and the United States. The survival rate of children and adolescents has increased immensely in developed countries, whereas the survival rate for adults lagged behind. The increase in the pediatric survival rate is attributable to the institution of hydroxyurea treatment as well as stroke prevention strategies. In this review, we discuss the management of the sickle disease major complications such as pain, stroke, and acute chest syndrome with the most current hydroxyurea use and transfusion therapy.     

Extreme hyperbilirubinemia: An indicator of morbidity and mortality in sickle cell disease

BACKGROUND Sickle cell disease(SCD) is a disorder that results in increased hospitalizations and higher mortality. Advances in management have resulted in increases in life expectancy and led to increasing awareness of sickle cell hepatopathy(SCH).However, its impact in patients on the natural history and outcomes of SCD is not known. Our study aims to describe the prevalence of extreme hyperbilirubinemia(EH), one form of SCH, its effect on morbidity and mortality,and correlations between sickle cell genotype and SCH type. We hypothesize that EH is associated with higher morbidity and mortality.AIM To investigate the effects of EH on morbidity and mortality among patients with SCD.METHODS This retrospective cohort study was performed using a database of patients with SCD treated at Grady Memorial Hospital between May 2004 and January 2017.Patients with EH(defined as total bilirubin above 13.0 mg/dL) were identified. A control group was identified from the same database with patients with total serum bilirubin ≤ 5.0 mg/dL. Electronic medical records were used to extract demographic information, laboratory values, radiology results, current medications, need for transfusions and mortality data. Two samples T-test, chi-squared test and Fisher's exact test were then used to compare the parameters between the two groups.RESULTS Out of the database, fifty-seven charts were found of patients with bilirubin 13 mg/dL. Prevalence of severe SCH as defined by EH was 4.8%(57/1172). There were no demographic differences between patients with and without EH.Significant genotypic differences existed between the two groups, with hemoglobin SS SCD being much higher in the EH group(P 0.001). Patients with severe EH had a significant elevations in alanine aminotransferase(157.0 ± 266.2 IU/L vs 19.8 ± 21.3 IU/L, P 0.001), aspartate aminotransferase(256.5 ± 485.9 U/L vs 28.2 ± 14.7 U/L, P 0.001) and alkaline phosphatase(218.0 ± 176.2 IU/L vs 85.9 ± 68.4 IU/L, P 0.001). Patients with EH had significantly higher degree of end organ failure measured with quick Sequential Organ Failure Assessment scores(0.42 ± 0.68 vs 0.01 ± 0.12, P 0.001), increased need for blood products(63% vs 5%, P 0.001), and exchange transfusions(10.5% vs 1.3%, P = 0.022).CONCLUSION Among patients with SCD, elevated levels of total bilirubin are rare, but indicative of elevated morbidity, mortality, and need for blood transfusions.Large differences in sickle cell genotype also exist, but the significance of this is unknown.     

Risky behaviours of Jamaican adolescents with sickle cell disease

Objectives

To describe the risky behaviours of Jamaican teens with sickle cell disease (SCD) and compare them to a national sample of Jamaican youth.

Methods

One hundred twenty two SCD adolescents, 15–19 years old, completed the standardized questionnaire used in the Jamaican Youth Risk and Resiliency Behaviour Survey (JYRRBS), which was a nationally representative survey of 1317 Jamaican youths. Information was obtained on socio-demographics, smoking, alcohol use, and sexual activity. Secondary data from the JYRRBS were extracted to measure the difference in risky behaviours between the groups.

Results

Almost 50% of SCD and 58% of national teens reported having had sexual intercourse. More SCD teens used alcohol (77.7% vs. 60.7%; P value = 0.001). Risky behaviours tended to coexist and living with a parent (odds ratio: 0.62, P value <0.01) and currently attending school (odds ratio: 0.43, P value <0.001) lowered the likelihood of having had sex.

Discussion

SCD teens engage in many risky behaviours and health care professionals should screen and counsel them at each visit.     

Management of sickle cell disease from childhood through adulthood

Sickle cell disease (SCD) is a genetic disorder characterised by anaemia and “sickling” of red blood cells, leading to chronic haemolytic anaemia, vascular injury, and organ dysfunction. Although children and adults experience many similar symptoms and problems, complications increase with age, leading to early mortality. Hydroxyurea (hydroxycarbamide), the only US Food and Drug Administration-approved treatment, continues to be under-utilised and other treatments available to children are often inaccessible for adults. Haematopoietic stem-cell transplantation is a curative option, but is limited by a lack of donors and concerns for transplant-related toxicities. Although comprehensive programs exist in paediatrics, affected adults may not have access to preventative and comprehensive healthcare because of a lack of providers or care coordination. They are often forced to rely on urgent care, leading to increased healthcare utilisation costs and inappropriate treatment. This problem highlights the importance of primary care during the transition from paediatrics to adulthood.     

Association between endothelial dysfunction and otoneurological symptoms in children with sickle cell disease

Objective: To evaluate the association between endothelial dysfunction and otoneurological symptoms and vaso-occlusive phenomena in children with sickle cell disease (SCD).

Methods: Cross-sectional study with 54 children, aged between 6 and19 years of age, of whom 28 had genotype SS and 26 apparently healthy (AA genotype) whose parents or guardians, or the children themselves, filled out a questionnaire designed to assess their otoneurological symptoms. All the individuals were submitted assessment of endothelial function by flow-mediated dilation (FMD) percentage with reactive hyperemia of brachial artery Doppler.

Results: Otoneurological symptoms (tinnitus and/or vertigo) predominated in the SCD group (46.4 vs. 15.4%; p?=?0.006). A negative correlation was observed between FMD percentage and time of evolution of vertigo SCD (r?=??0.432; p?=?0.022) and the linear regression analysis demonstrated that for every reduction in FMD percentage there was an increase in time of evolution of vertigo of 1.79 months (β?=??1.79; p?=?0.022). The positive correlation between episodes of painful crisis and time of evolution of vertigo (r?=?0.3; p?=?0.04).

Discussion: The presence of vascular endothelial damage in the labyrinthine artery in patients with SCD is capable of compromising the semicircular canals, shown by clinical expression of otoneurological symptoms, such as vertigo. In the present study, an association was observed between endothelial dysfunction with otoneurological symptoms and otoneurological symptoms and vaso-occlusive phenomena in SCD.     

Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease

Background

As would be expected with a hypercoagulable state, pulmonary embolism (PE) occurs in sickle cell disease (SCD). Its frequency, however, is undetermined, largely because of difficulties in distinguishing it from thrombosis in situ. The prevalence of deep venous thrombosis (DVT) is also undetermined in patients with SCD. Knowing the prevalence of DVT would be an important step in the overall assessment of the risk of PE in these patients.

Methods

Data from the National Hospital Discharge Survey were assessed.

Results

In patients <age 40 years, 7000 of 1,581,000 (0.44%) with SCD had a discharge diagnosis of PE compared with 59,000 of 48,611,000 (0.12%) of African Americans without SCD. The prevalence of DVT was similar in patients < age 40 with SCD, 7000 of 1,581,000 (0.44%) and in African Americans who did not have SCD, 193,000 of 48,611,000 (0.40%).

Conclusion

The high prevalence of apparent PE in patients with SCD, compared with non-SCD African-American patients of the same age and the comparable prevalence of DVT in both groups are compatible with the concept that thrombosis in situ might be present in many. On the other hand, the data suggest that PE is not rare in patients with SCD. This suggests that PE might be an etiologic factor in patients with SCD who develop respiratory symptoms. In such patients, an imaging procedure might be appropriate.