Clinical, laboratory, and genetic risk factors for thrombosis in sickle cell disease

Srisuwananukorn, Andrew; Raslan, Rasha; Zhang, Xu; Shah, Binal N.; Han, Jin; Gowhari, Michel; Molokie, Robert E.; Saraf, Santosh L.

doi:10.1182/bloodadvances.2019001384

Cited by 34 publications

(40 citation statements)

References 52 publications

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“…Risk factors for VTE in SCD include increased disease severity (as measured by averaging ≥3 hospital admissions a year for VOC), exposure to erythropoiesis stimulating agents or blood transfusion, insertion of central venous catheters (CVC), surgical splenectomy, and hospitalization. [21][22][23][24] As mentioned above, not only are SCD patients at a high risk for developing early onset VTE, but their risk for VTE recurrence after an index VTE has been noted to be high. Clinical risk factors for VTE recurrence include averaging >3 hospital admissions a year, lower extremity DVT as the index event, and a prior history of pneumonia/acute chest syndrome (ACS).…”

Section: Clinical and Genetic Risk Factors For The Prothrombotic Statementioning

confidence: 97%

“…Clinical risk factors for VTE recurrence include averaging >3 hospital admissions a year, lower extremity DVT as the index event, and a prior history of pneumonia/acute chest syndrome (ACS). 8,23 Incomplete adherence to anticoagulation is also likely to contribute to higher recurrence rates, though this has not been formally evaluated. In a single center retrospective study, use of direct oral anticoagulants (DOAC) was associated with lower recurrence rate.…”

Section: Clinical and Genetic Risk Factors For The Prothrombotic Statementioning

confidence: 99%

“…In a single center retrospective study, use of direct oral anticoagulants (DOAC) was associated with lower recurrence rate. 23 Genotype may also modify thrombotic risk in SCD. Certainly, children with HbSS/Sβ 0 are at highest risk for arterial thrombosis such as stroke.…”

Section: Clinical and Genetic Risk Factors For The Prothrombotic Statementioning

confidence: 99%

“…Aim: Investigate the genetic and clinical predictors of VTE risk was independently associated with HbSS/Sβ 0 et al 23 arterial and venous thrombosis in SCD. genotype, HU use, lower estimated glomerular filtration rate, Longitudinal single center cohort study.…”

Section: Srisuwananukornmentioning

confidence: 99%

“…8 Similarly, smaller retrospective studies indicate that all anticoagulants have an increased bleeding risk, with DOAC having the least risk. 23,125,126 In spite of these advantages, the exact role for DOAC in the management of VTE in SCD patients is not clear.…”

Section: Managing Venous Thrombosis In Sickle Cell Diseasementioning

confidence: 99%

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The molecular basis for the prothrombotic state in sickle cell disease

2020

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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.

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Section: Clinical and Genetic Risk Factors For The Prothrombotic Statementioning

confidence: 97%

Section: Clinical and Genetic Risk Factors For The Prothrombotic Statementioning

confidence: 99%

Section: Clinical and Genetic Risk Factors For The Prothrombotic Statementioning

confidence: 99%

Section: Srisuwananukornmentioning

confidence: 99%

Section: Managing Venous Thrombosis In Sickle Cell Diseasementioning

confidence: 99%

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The molecular basis for the prothrombotic state in sickle cell disease

2020

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Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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