The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial protective effects in the ...heterozygous state. In 1949, homozygous Hb S or sickle cell disease (SCD) became the first inherited condition identified at the molecular level; however, since then, both SCD and heterozygous Hb S, sickle cell trait (SCT), have endured a long and complicated history. Hasty adoption of early mass screening programs for SCD, recent implementation of targeted screening mandates for SCT in athletics, and concerns about stigmatization have evoked considerable controversy regarding research and policy decisions for SCT. Although SCT is a largely protective condition in the context of malaria, clinical sequelae, such as exercise-related injury, renal complications, and venous thromboembolism can occur in affected carriers. The historical background of SCD and SCT has provided lessons about how research should be conducted in the modern era to minimize stigmatization, optimize study conclusions, and inform genetic counseling and policy decisions for SCT.
The genetic and molecular basis of sickle cell disease (SCD) has long since been characterized but the pathophysiological basis is not entirely defined. How a red cell hemolytic disorder initiates ...inflammation, endothelial dysfunction, coagulation activation and eventually leads to vascular thrombosis, is yet to be elucidated. Recent evidence has demonstrated a high frequency of unprovoked/recurrent venous thromboembolism (VTE) in SCD, with an increased risk of mortality among patients with a history of VTE. Here, we thoroughly review the molecular basis for the prothrombotic state in SCD, specifically highlighting emerging evidence for activation of overlapping inflammation and coagulation pathways, that predispose to venous thromboembolism. We share perspectives in managing venous thrombosis in SCD, highlighting innovative therapies with the potential to influence the clinical course of disease and reduce thrombotic risk, while maintaining an acceptable safety profile.
Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent ...throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.
COVID-19 outcomes in sickle cell disease and sickle cell trait Christian, Jana; Lanzkron, Sophie; Naik, Rakhi P.
Baillière's best practice and research in clinical haematology/Baillière's best practice & research. Clinical haematology,
09/2022, Letnik:
35, Številka:
3
Journal Article
Recenzirano
Odprti dostop
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.
Patients on dialysis are known to have higher risk for gastrointestinal (GI) bleeding. However, data on mild to moderate CKD, particularly elevated albuminuria, are limited.
Among 11,088 participants ...in the Atherosclerosis Risk in Communities (ARIC) Study, we investigated the association of eGFR and urinary albumin-to-creatinine ratio (ACR) with risk for hospitalization with GI bleeding. Kidney measures were assessed at visit four (1996-1998), and follow-up was continued through 2011.
During a median follow-up of 13.9 years, 686 first incident hospitalizations with GI bleeding were observed (incidence rate, 4.9 per 1000 person-years 95% confidence interval (95% CI), 4.5 to 5.3). Multivariable Cox proportional hazards models revealed that both lower eGFR and higher ACR were associated with higher risk for GI bleeding. With eGFR≥90 ml/min per 1.73 m
as a reference, risk for GI bleeding was significant in moderately decreased eGFR of 30-59 ml/min per 1.73 m
(hazard ratio HR, 1.51; 95% CI, 1.13 to 2.02), and was highest in severely decreased eGFR<30 ml/min per 1.73 m
(HR, 7.06; 95% CI, 3.91 to 12.76). Compared with ACR<10 mg/g, risk for GI bleeding became significantly higher in mild albuminuria with ACR 10-29 mg/g (HR, 1.36; 95% CI, 1.08 to 1.69), and was nearly double in moderate and severe albuminuria (HR, 2.13; 95% CI, 1.66 to 2.71 for ACR 30-299 mg/g, and HR, 2.07; 95% CI, 1.33 to 3.22 for ACR≥300 mg/g). These results were largely consistent in demographic and clinical subgroups and independent of incident cardiovascular events or dialysis during follow-up.
Individuals with even mild to moderate CKD warrant clinical attention regarding the risk of hospitalization with GI bleeding.
Abstract Background Sickle cell disease is recognized as a hypercoagulable state; however, the frequency and characteristics of venous thromboembolism in sickle cell patients have not been well ...defined. The purpose of this study was to establish the prevalence and risk factors for venous thromboembolism in a large cohort of patients with sickle cell disease and determine the relationship between venous thromboembolism and mortality. Methods We performed a cross-sectional study of 404 sickle cell disease patients cared for at the Sickle Cell Center for Adults at Johns Hopkins. Demographic, sickle cell disease-specific comorbidity, and venous thromboembolism data were collected on all patients. Results One hundred one patients (25%) had a history of venous thromboembolism with a median age at diagnosis of 29.9 years. A history of non-catheter-related venous thromboembolism was found in 18.8% of patients. Sickle variant genotypes conferred a higher risk of non-catheter-related venous thromboembolism compared with sickle cell anemia genotypes (SS/Sβ0 ) (relative risk RR 1.77; 95% confidence interval CI, 1.18-2.66). Tricuspid regurgitant jet velocity ≥2.5 m/s also was associated with non-catheter-related venous thromboembolism (RR 1.65; 95% CI, 1.12-2.45). Thirty patients (7.4%) died during the study period. Adjusting for all variables, non-catheter-related venous thromboembolism was independently correlated with death (RR 3.63; 95% CI, 1.66-7.92). Conclusion Venous thromboembolism is common in adults with sickle cell disease. Sickle variant genotypes and tricuspid regurgitant jet velocity ≥2.5 m/s are associated with non-catheter-related venous thromboembolism. In addition, non-catheter-related venous thromboembolism appears to be an independent risk factor for death in our cohort. These results suggest that disease-specific prophylaxis and treatment strategies for venous thromboembolism should be investigated in sickle cell disease patients.
Immune checkpoint blockade has demonstrated durable clinical benefits in a variety of malignancies. These immune checkpoint inhibitors (ICIs) produce unwanted autoimmune reactions due to an impaired ...self-tolerance. Hematologic immune-related adverse events (heme-irAEs) have been increasingly reported in the literature with a reported fatality rate of 12%. In this review, we illustrate 3 cases treated at Johns Hopkins Hospital for ICI-induced agranulocytosis, aplastic anemia, and thrombocytopenia. We then summarize the available evidence regarding the incidence and prevalence of heme-irAEs. We identified immune thrombocytopenia and hemolytic anemia as the most commonly reported heme-irAEs which are more commonly observed with nivolumab therapy. Median time to onset of heme-irAEs varies between patients but occurs earlier with CTLA-4 inhibitors than with anti-PD-L1/PD-1 agents. We also describe the current challenges regarding the recurrence of heme-irAEs despite immune checkpoint blockade termination. We provide the available evidence supporting a mixed T-cell and B-cell immune-mediated response. Finally, we review the treatment algorithm of these complications and provide treatment alternatives to steroid-refractory cases.
Thrombosis-thrombocytopenia syndrome and cerebral venous sinus thrombosis have been rarely reported in patients who have received severe acute respiratory syndrome coronavirus 2 adenoviral vector ...vaccines. Awareness of this potential adverse effect, recognizing early clinical symptoms and subtle signs of cerebral venous sinus thrombosis on head computed tomography and brain magnetic resonance imaging, appropriate vascular imaging, and unique treatment for this condition is critical. This is a report of a case of vaccine-induced thrombotic thrombocytopenia and associated cerebral venous sinus thrombosis with emphasis on imaging and clinical course.
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