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      Sickle cell disease, sickle trait and the risk for venous thromboembolism: a systematic review and meta-analysis

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          Abstract

          Background

          Globally, sickle cell disease (SCD) is one of the most common haemoglobinopathy. Considered a public health problem, it leads to vessel occlusion, blood stasis and chronic activation of the coagulation system responsible for vaso-occlussive crises and venous thromboembolism (VTE) which may be fatal. Although contemporary observational studies suggest a relationship between SCD or sickle trait (SCT) and VTE, there is lack of a summary or meta-analysis data on this possible correlation. Hence, we propose to summarize the available evidence on the association between SCD, SCT and VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE).

          Methods

          We searched PubMed and Scopus to identify all cross-sectional, cohort and case-control studies reporting on the association between SCD or SCT and VTE, DVT or PE in adults or children from inception to April 25, 2017. For measuring association between SCD or SCT and VTE, DVT, or PE, a meta-analysis using the random-effects method was performed to pool weighted odds ratios (OR) of risk estimates.

          Results

          From 313 records initially identified from bibliographic databases, 10 studies were eligible and therefore included the meta-analysis. SCD patients had significantly higher risk for VTE (pooled OR 4.4, 95%CI 2.6–7.5, p < 0.001), DVT (OR 1.1, 95% CI 1.1–1.2, p < 0.001) and PE (pooled OR 3.7, 95% CI 3.6–3.8, p < 0.001) as compared to non SCD-adults. A higher risk of VTE (OR 33.2, 95% CI 9.7–113.4, p < 0.001) and DVT (OR 30.7, 95% CI 1.6–578.2, p = 0.02) was found in pregnant or postpartum women with SCD as compared to their counterparts without SCD. Compared to adults with SCT, the risk of VTE was higher in adults with SCD (pooled OR 3.1, 95% CI 1.8–5.3, p < 0.001), and specifically in SCD pregnant or postpartum women (OR 20.3, 95% CI 4.1–102, p = 0.0003). The risk of PE was also higher in adults with SCD (OR 3.1, 95% CCI 1.7–5.9, p = 0.0004) as compared to those with SCT. The risk of VTE was higher in individuals with SCT compared to controls (pooled OR 1.7, 95% CI 1.3–2.2, p < 0.0001), but not in pregnant or postpartum women (OR 0.9, 95% CI 0.3–2.9, p = 0.863). Compared to controls, SCT was associated with a higher risk of PE (pooled OR 2.1, 95% CI 1.2–3.8, p = 0.012) but not of DVT (pooled OR 1.2, 95% CI 0.9–1.7, p = 0.157).

          Conclusion

          Individuals with SCD, especially pregnant or postpartum women, might have a higher risk of VTE compared to the general population. SCT might also increases the risk of VTE. However, currently available data are not sufficient to allow a definite conclusion. Further larger studies are needed to provide a definitive conclusion on the association between SCD, SCT and VTE.

          Electronic supplementary material

          The online version of this article (10.1186/s12959-018-0179-z) contains supplementary material, which is available to authorized users.

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          Most cited references 31

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          Epidemiology of venous thromboembolism.

           John Heit (2015)
          Thrombosis can affect any venous circulation. Venous thromboembolism (VTE) includes deep-vein thrombosis of the leg or pelvis, and its complication, pulmonary embolism. VTE is a fairly common disease, particularly in older age, and is associated with reduced survival, substantial health-care costs, and a high rate of recurrence. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and various risk factors. Major risk factors for incident VTE include hospitalization for surgery or acute illness, active cancer, neurological disease with leg paresis, nursing-home confinement, trauma or fracture, superficial vein thrombosis, and-in women-pregnancy and puerperium, oral contraception, and hormone therapy. Although independent risk factors for incident VTE and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be fairly constant, or even increasing.
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            Thrombosis: a major contributor to the global disease burden.

            (2014)
            Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2010 documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden caused by VTE in low-income, middle-income and high-income countries. Studies from western Europe, North America, Australia and southern Latin America (Argentina) yielded consistent results, with annual incidence rates ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥ 70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low, because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years (DALYs) lost in low-income and middle-income countries, and the second most common cause in high-income countries, being responsible for more DALYs lost than nosocomial pneumonia, catheter-related bloodstream infections, and adverse drug events. VTE causes a major burden of disease across low-income, middle-income and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate whether improved utilization of preventive measures will reduce the burden.
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              Complications associated with sickle cell trait: a brief narrative review.

              Sickle cell trait occurs in approximately 300 million people worldwide, with the highest prevalence of approximately 30% to 40% in sub-Saharan Africa. Long considered a benign carrier state with relative protection against severe malaria, sickle cell trait occasionally can be associated with significant morbidity and mortality. Sickle cell trait is exclusively associated with rare but often fatal renal medullary cancer. Current cumulative evidence is convincing for associations with hematuria, renal papillary necrosis, hyposthenuria, splenic infarction, exertional rhabdomyolysis, and exercise-related sudden death. Sickle cell trait is probably associated with complicated hyphema, venous thromboembolic events, fetal loss, neonatal deaths, and preeclampsia, and possibly associated with acute chest syndrome, asymptomatic bacteriuria, and anemia in pregnancy. There is insufficient evidence to suggest an independent association with retinopathy, cholelithiasis, priapism, leg ulcers, liver necrosis, avascular necrosis of the femoral head, and stroke. Despite these associations, the average life span of individuals with sickle cell trait is similar to that of the general population. Nonetheless, given the large number of people with sickle cell trait, it is important that physicians be aware of these associations.
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                Author and article information

                Contributors
                noubiapjj@yahoo.fr
                neurotemgoua@yahoo.fr
                ronnitank@gmail.com
                joeltochie@gmail.com
                ambroise.wonkam@uct.ac.za
                bignarimjj@yahoo.fr
                Journal
                Thromb J
                Thromb J
                Thrombosis Journal
                BioMed Central (London )
                1477-9560
                4 October 2018
                4 October 2018
                2018
                : 16
                Affiliations
                [1 ]ISNI 0000 0004 1937 1151, GRID grid.7836.a, Department of Medicine, , Groote Schuur Hospital and University of Cape Town, ; Cape Town, 7925 South Africa
                [2 ]ISNI 0000 0001 2173 8504, GRID grid.412661.6, Department of Internal Medicine and sub-Specialties, Faculty of Medicine and Biomedical Sciences, ; Yaoundé, Cameroon
                [3 ]ISNI 0000 0001 2173 8504, GRID grid.412661.6, Department of Surgery and sub-Specialties, Faculty of Medicine and Biomedical Sciences, ; Yaoundé, Cameroon
                [4 ]ISNI 0000 0004 1937 1151, GRID grid.7836.a, Division of Human Genetics, Faculty of Health Sciences, , University of Cape Town, ; Cape Town, South Africa
                [5 ]Department of Epidemiology and Public Health, Centre Pasteur of Cameroon, Yaoundé, Cameroon
                [6 ]ISNI 0000 0001 2171 2558, GRID grid.5842.b, Faculty of Medicine, , University of Paris Sud XI, ; Le Kremlin Bicêtre, France
                Article
                179
                10.1186/s12959-018-0179-z
                6171302
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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