Summary Spin density projection‐assisted R 2‐magnetic resonance imaging ( R 2‐ MRI ; F erriScan ® ) scans from 40 chelation‐naïve sickle cell patients were used to assess renal iron load by measuring renal R 2 ( R ‐ R 2). Clinical data were collected retrospectively for the 2‐year period preceding the scan. R ‐ R 2 showed no significant correlation with transfusional iron load (assessed by liver iron concentration), but correlated significantly with serum bilirubin ( R = 0·61, P < 0·0001) and lactate dehydrogenase ( R = 0·58, P < 0·0001). Mean (±standard deviation) R ‐ R 2 was higher ( P = 0·02) in patients with renal hyperfiltration (29·8 ± 10·3/s) than those without (23·11 ± 6·6/s). Five patients had significantly lower signal intensity in the renal cortex, as compared to the medulla. These patients had a significantly higher ( P < 0·0001) mean R ‐ R 2 than those showing no cortico‐medullary difference. We postulate that the increased R ‐ R 2 is associated with haemolysis rather than transfusional iron load in sickle cell disease.
This guideline was compiled according to the British Society of Haematology (BSH) process at https://b-s-h.org.uk/media/19922/bsh-guidance-development-process-july-2021.pdf. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org and the literature search is summarised in Appendix. A review of the manuscript was performed by the BSH Haematology General Haematology Task Force, the BSH Guidelines Committee and the sounding board of BSH. It was also placed on the members section of the BSH website for comment. Sickle cell disease (SCD) (sickle cell anaemia and related compound heterozygous states) manifests as a hypercoagulable state with high levels of chronic platelet activation, thrombin generation and inflammation. Venous thromboembolism (VTE) has been increasingly recognised as a common comorbidity in comprehensive reviews of SCD, with rates particularly increased when other risk factors for VTE are also present. Regular red cell transfusion is an essential therapy for a subpopulation of patients with SCD or thalassaemia. The need for regular venous access can become challenging for a variety of reasons (e.g. poor peripheral veins or intense needle phobia, especially in children), but attempts to persevere with this option should always be explored, including ultrasound-guided cannulation or psychotherapy as indicated. Nonetheless, temporary or long-term central venous access devices (CVADs) can become a necessity. Temporary line insertion on the day of procedure, especially insertion of femoral central venous catheters (CVCs), is associated with increased rates of infective complications, bleeding risk and progressive tissue scarring making repeat insertion increasingly complex.1 Furthermore, in some cases, venous access may be required at other times for patient care, for example, ongoing chelation therapy. Indwelling CVADs (CVCs) require a surgical procedure for insertion, but have lower infection rates and present much simpler and quicker access on transfusion days and at other times. These are often therefore the preferred option for this patient cohort. However, catheter-associated VTE is a common and significant complication in these patients. Guidance for consideration of prophylactic anticoagulation to mitigate this risk has been developed based on published literature evidence. Catheter-associated VTE was defined in most studies as a radiologically confirmed diagnosis of catheter-related thrombosis, right atrial or ventricular thrombus, upper or lower limb deep vein thrombosis (DVT), pulmonary embolism (PE) or VTE at other sites, confirmed by diagnostic imaging such as Doppler ultrasound, echocardiogram or computed tomography-pulmonary angiogram. Based on retrospective studies, VTE has been shown to affect up to a quarter of adult SCD patients and is a risk factor for early mortality.2 In a cross-sectional study of 404 SCD patients cared for at a quaternary centre in the United States, Naik et al. found that 25% of adult patients with SCD have a history of a VTE, a prevalence that is similar to that seen in patients with recognised thrombophilic states such as antithrombin, protein C or protein S deficiency (21%).3 The largest study performed using the National Hospital Discharge Survey evaluated 1 804 000 SCD admissions from 1979 to 2003 and found that the prevalence of PE in hospitalised SCD patients <40 years of age was approximately 3.5 times higher than in African–American controls,4 while VTE incidence in patients with SCD is reported at 5.2 events/1000 person years with a cumulative occurrence of 11.3% by age 40 years.5, 6 Patients with SCD have a number of additional risk factors for VTE, including frequent hospitalisation, high-risk surgery such as orthopaedic surgery for avascular necrosis, pregnancy and use of indwelling CVCs.2, 7 Brunson et al.,5, 6 demonstrated in their study that the VTE risk associated with SCD and multiple hospital admissions is greater than that conferred by multiple hospital admission alone as demonstrated versus matched controls. Thus, SCD represents a pro-thrombotic state with a VTE risk 2.6 times greater than the general population8 and 50 times greater than the quoted risk for under 40 year olds without SCD.9 Patients with thalassaemia are also recognised to have a hypercoagulable state. A paediatric study found 4% of 683 patients with transfusion-dependent beta-thalassaemia major (TDT) and 9.6% of 52 patients with non-transfusion-dependent thalassaemia (NTDT) had VTE events,10 while another study showed VTE affected up to 14% of the study population.11 The main independent risk factors for thrombotic events were splenectomy, iron overload (serum ferritin level >1000 ng/mL), age older than 35 years, and a haemoglobin concentration of less than 90 g/L.11 In a separate study of splenectomised patients, the occurrence of VTE was 29% demonstrating how high risk this sub-cohort is.12 Central venous catheters are commonly used in SCD and can be a significant risk factor for VTE. A large cross-sectional study demonstrated that 30% of all episodes of VTE in a cohort of 404 patients with SCD were catheter-associated, although the study did not provide information on the total number of different patients affected versus recurrent events in an individual.3 The literature includes a range of multicentre and single-centre retrospective studies that look to quantify the incidence of thrombosis in SCD. These report that between 3% and 41% of CVCs are complicated by VTE with an incidence ranging from 0.14 to 0.99 VTE events per 1000 catheter days.7, 13-18 These studies typically include small patient numbers and lack consistency, making firm conclusions difficult to establish. They report on different types of CVC, from peripherally inserted central catheters (PICC) lines and temporary femoral CVC lines, to totally implantable venous access devices (TIVAD) such as single- and dual-lumen Port-a-caths. When considering the adult population only, the catheter-related thrombus (CRT) occurrence per catheter is higher at 19%–41%.14, 18-21 This even included asymptomatic line-associated right atrial thrombus, detected by echocardiogram or cardiac magnetic resonance imaging. Although the majority of these events are reported in patients with haemoglobin SS or Sβ thalassaemia0, reflecting the high use of catheters in more severe genotypes, they were also reported in patients with other genotypes of SCD.18 Only two studies were identified reporting on the occurrence of CRT-associated VTE in patients with thalassaemia. Both these studies looked at patients in teenage and young adult age groups. They identified a VTE occurrence that ranged from 32% to 57% in patients with an incidence of 0.41 to 0.48 per 1000 catheter days.22, 23 Studies in adults report a higher rate of thrombosis than in paediatric populations (Table 1). It is well recognised that thrombotic risk increases with age. There is an accumulation of associated comorbidities, vascular endothelial damage and increased inflammation leading to a heightened procoagulant state. This increased VTE risk was also identified in the context of CRT in patients with SCD in studies by Shah et al., Woods et al. and Forté et al.18, 21, 24 40% (n = 10/25) without thromboprophylaxis versus 16% (n = 4/24) in with thromboprophylaxis 0.44 without thromboprophylaxis Versus 0.13 with thromboprophylaxis 23.8% (n = 5/21) 28% (n = 5/18) without thromboprophylaxis 0% (n = 0/3) with thromboprophylaxis 12.5% (n = 3/24 CVADs)/18.75% (n = 3/16) In the general population, the occurrence of VTE in children is exceedingly low (0.007 to 0.014 per 1000) and 0.53 VTE/1000 in paediatric hospital admissions.25 There is a bimodal VTE risk profile in paediatrics, with a VTE rate of 14.5 per 10 000 per year in the neonatal period, and among adolescents (aged 15–17 years) the rate is quoted at 1.1 per 10 000 per year.26 It is reported that more than 90% of VTE in children are associated with CVC.27 The rate of VTE in children with SCD with CVCs was harder to identify as several studies grouped the data or had a mixed-age patient group of both children and young adults.15-17, 28 Woods et al. performed a single-centre US retrospective study of VTE in children with SCD. They demonstrated that CVC use is an independent and primary predictor of VTE (p < 0.001)24 and reported a cumulative CRT rate of 22% per person with CVCs in-situ in their paediatric cohort.24 However, they observed the patients with CVC-associated VTE were found to be significantly older when compared with the patients without VTE (15.9 years vs. 11.8 years, p = 0.03).24 Shah et al. reported a rate of 41% in their adult cohort, but only 10% in the paediatric patients. Jeng et al. reported that 33% of patients had a catheter-related thrombotic event at a rate of 0.99 per 1000 catheter days. The patients were aged 1.4–30 years; although the age of those with thrombotic events was not reported.15 Bartram et al. found no thrombotic events in their 9-year single-centre retrospective analysis of children aged 3–15 years of age.29 Abdul-Rauf et al. reported 8% of their 25 patients with TIVADs had thrombotic complications, at a rate of 0.29 per 1000 catheter patient days.17 They found an overall VTE occurrence of 2.8% in this cohort of 414 patients, of which 75% were CVC-associated (odds ratio [OR] 33.8, 95% confidence interval [CI] 8.7–130.9; p < 0.001) and the mean age at VTE-event was 15.9 years. Ordonez et al. report on a cohort of 54 paediatric patients with SCD or thalassaemia major (TM).28 Most of these patients had single-lumen TIVADs in situ. They reported a per-person thrombosis rate of 7.4%, and showed the thrombotic rate to be 0.038 per 1000 catheter days with single-lumen TIVADs. Ilonze et al. found similarly low thrombotic rates in children with SCD with an incidence of catheter-related VTE of 0.03 per 1000 catheter days. In this cohort, single-lumen infusion ports were used exclusively. de Boechat et al. also reported a very low VTE occurrence in their paediatric retrospective study of 1063 children with SCD at 0.2%, and both these were CVC-associated (p < 0.001).30 In these studies, the occurrence of VTE in children and young adults (under 30) with CVCs in these studies was 0%–33%. More recent studies that included only paediatric patients show a far lower rate of thrombosis of 0.03–0.29 per 1000 catheter days.28, 31 The rate of thrombosis in studies that included adolescents and young adults was higher. In addition, these older children and young adults often require dual-lumen devices to facilitate automated red cell exchange transfusion, and such devices may also carry a greater thrombotic risk. In conclusion, the presence of CVC is associated with a significant VTE risk in adults and adolescents with SCD. This mirrors the wider population of patients with SCD, where the risk of VTE increases from teenage years and into adulthood. The site of line insertion, tip position and the type of line used are all factors that influence VTE rates. A number of the paediatric and adolescent studies demonstrated that dual-lumen TIVADs were associated with higher thrombotic rates than single-lumen TIVADs.24, 28, 29, 31 However, this may also be because dual-lumen ports would be sited in preference to single-lumen ports for older children undergoing red cell exchange, rather than simple top up transfusion. Shah et al. reported no difference between dual- or single-lumen devices in their adult retrospective study.18 Sharma et al. and Woods et al. found bilateral CVC placement to be an independent risk factor for VTE.24, 32 It is difficult to compare types of port used across different studies, however, Forté et al. found the use of Port-a-cath CVCs to be associated with lower thrombotic risk than other types of CVAD including PICCs, Vortex and Xcela Power lines (risk ratio [RR] = 5.8 [1.3–25.9], p = 0.02, and RR = 58.2 [15.0–225.0], p < 0.001 respectively).20 This trend is also demonstrated in Table 1 where studies that solely focus on Port-a-Cath generally have lower rates of VTE associated with CVC use. In addition, both Forté et al. and Brewin et al. identified an 8%–10% occurrence of asymptomatic right atrial thrombus with the Vortex ports. Brewin et al., went on to examine tip positioning and suggested those lying deeper into the right atrium were more strongly associated with atrial thrombus formation (3 out of 7) than those positioned at the cavo-atrial junction or proximal right atrium (0 out of 9).20 In Forté et al.'s study, hydroxycarbamide (hydroxyurea) usage was associated with significantly lower VTE rates in adult patients with SCD (RR = 20.5 [6.4–65.3], p < 0.001). As a retrospective study, it is difficult to know how to appraise this finding. As the authors themselves note, other retrospective studies have found hydroxyurea to be positively associated with VTE rates.20 Additional co-morbidities and events can increase the VTE risk in this cohort. Some of these are based on population-wide risk factors such as inherited thrombophilia, obesity and recent hospital admission.21 Others are more specific to SCD. It is difficult to derive strong evidence to support these conclusions from the published CRT datasets as they are small and retrospective. Further support can be gained from the analysis of VTE risk in the total SCD cohort. Woods et al. found the haemoglobin SS genotype to be significantly associated with VTE (when compared with all other genotypes) (OR 10.7, 95% CI 1.4–83.5; p = 0.006). They also reported central nervous system vasculopathy (OR 19.4, 95% CI 5.6–63.4; p < 0.001), and chronic transfusion therapy (OR 30.6, 95% CI 8.9–122.2; p < 0.001)24 to significantly increase the risk, although these were not significant in multivariate analysis, likely because they over-represented the cohort with a CVC in situ. Only CVC in situ remained independently associated with VTE (OR 33.8, 95% CI 8.7–130.9).24 Naik et al. report that evidence of pulmonary hypertension as defined as a tricuspid regurgitant jet >2.5 m/s on transthoracic echocardiogram, was associated with increased thrombotic risk (RR 1.65; 95% CI, 1.12–2.45). A history of splenectomy7, 33 has also been found to increase VTE risk. This is a recognised complication with splenectomy outside of the context of SCD.2, 7 In conclusion, patients with CVCs are at higher risk of VTE if they have evidence of pulmonary hypertension, previous splenectomy or previous VTE. They are at short-term increased risk if they are experiencing concurrent illnesses such as sepsis, chest crisis, vaso-occlusive crisis or surgery or have additional markers of inflammation. Antithrombotic medications are well-known to be associated with an increased risk of bleeding. Several risk assessment tools have been developed to estimate this bleeding risk prior to the commencement of anticoagulation such as the HAS-BLED score, a very popular model which was developed based on the multivariate regression of the European Heart Survey database of atria.34 The other risk scoring tools are the HEMORR2HAGES, ATRIA, ORBIT and ABC-bleeding scores which can assist in the decision process of the risk–benefit balance of anticoagulation treatment.35 However, these risk scores, summarised in Table 2, were created and validated in patients with atrial fibrillation, while patient with SCD or thalassaemia with CVCs in situ who suffered VTE or are at risk for this complication are a clinically different cohort and also contain unique sickle bleeding characteristics. Clinical guidelines for VTE management do recommend assessment of bleeding prior to initiating anticoagulant treatment, but validated tools are not yet common-place.36 Experts suggest a detailed bleeding risk assessment to identify risk factors which can help in selecting the appropriate anticoagulant, can indicate what may be a safe dose for initial and extended treatment and the optimal treatment duration.34 The HAS-BLED or RIETE score has been used to identify patients at high risk of major bleeding during the initial VTE treatment phase, while the VTE-BLEED score has been used to decide on extended/long-term anticoagulation in this clinical scenario.37 General bleeding risk factors are detailed below as captured by the HAS-BLED, RIETE and VTE-BLEED.38 In addition, complications more unique to SCD and thalassaemia should be considered. Patients with SCD who have significant cerebrovascular disease, especially those with Moya Moya formation, are at significantly increased risk of intracerebral haemorrhage. Patients should also be assessed for evidence of active proliferative sickle retinopathy which predisposes to bleeding events. Despite the increased incidence of VTE in patients with SCD with CVCs in situ that has been recognised for many years, there is a lack of studies investigating the use of pharmacological thromboprophylaxis in this group. No specific anticoagulation practices or guidelines were identified by systematic literature review specific to SCD. Limitations to the body of evidence identified include their retrospective nature, the lack of randomised controlled trials to compare thromboprophylaxis in patients with SCD or thalassaemia with CVCs to those without. We identified only two retrospective cohort studies addressing this question: Forté et al. (n = 49) and Brewin et al. (n = 21).20, 21 Forté et al. performed a retrospective case–control study21 that specifically examined the rates of VTE in patients with SCD with CVCs with thromboprophylaxis versus without thromboprophylaxis. This multicentre international retrospective cohort study (n = 49 with CVC insertion) showed patients without thromboprophylaxis had higher VTE rates of 40% (n = 10/25) versus 16% (n = 4/24) in the patients who did receive thromboprophylaxis.21 In this study, thromboprophylaxis type and intensity varied widely. Treatment dose anticoagulation was used in 58% and included either low-molecular-weight heparin (LMWH), direct oral anticoagulant (DOAC) at approved treatment dosing or warfarin with a target international normalised ratio (INR) of 2.0–3.0. Thromboprophylaxis at reduced dosing (42%) was defined as either LMWH, DOAC at approved prophylactic dosing, or warfarin with a target of INR 1.5–2.5, or <2.0, or aspirin at any dose. On univariate analysis, the use of thromboprophylaxis was associated with a fourfold (1.2–12.6) reduction in the rate of VTE (p = 0.02) without adjustment for other confounding factors that are known VTE risk factors.21 On multivariable analysis, after adjustment for sex, age, additional VTE risk factors, hydroxyurea, thromboprophylaxis, body mass index and CVC subtype, the relative rate reduction of VTE with thromboprophylaxis was 14.9 (2.0–108.7) (p = 0.01).21 In a single-centre UK retrospective cohort study data of SCD patients, Brewin et al. gave a discrete breakdown of VTE events and thromboprophylaxis with CVCs data. They reported the VTE occurrence with venous catheter was 28% without thromboprophylaxis (n = 5/18) and no VTEs in the group who utilised thromboprophylaxis (n = 0/3) in their small study, although it should be noted that statistical significance was not calculated in this study due to the small sample size. In this very limited cohort on thromboprophylaxis, LMWH at prophylactic dosing was used for 6 weeks only after line insertion.20 These two studies offer some evidence of the protective effect of thromboprophylaxis in SCD patients with CVCs; however, we note the limitations of relying on two retrospective, non-randomised studies. There have been a number of larger studies investigating the use of prophylaxis in the cancer population and although the recent Cochrane review suggested that there may be some benefit in thromboprophylaxis with a meta-analysis reporting RR 0.43 (95% CI 0.22–0.81) reduction in CRT for those given LMWH prophylaxis versus those not.39 In addition, they reported no increase in major or minor bleeding.39 In addition, the use of pharmacological thromboprophylaxis was also reported to show a reduction in mortality by a separate meta-analysis of eight studies of a metastatic cancer population (n = 2639, RR = 0.58, 95% CI: 0.48–0.71).40 Except for a small number of patients with high bleeding risk complications, thromboprophylaxis prescription is likely to be a safe and beneficial intervention for these patients with CVCs. However, the duration and intensity of the thromboprophylaxis used are not clear cut. For primary prevention, prophylactic dosing is recommended, particularly in the setting of SCD where additional bleeding risks exist due to sickle retinopathy and cerebrovascular disease. For secondary prevention, Clark et al.41 showed that, in a non-SCD paediatric population, only full-dose anticoagulation was effective. The selection of the optimal level of anticoagulation for individuals will require careful consideration of their bleeding and thrombosis risk. There is limited evidence to support the use of any specific class of anticoagulant over another in this setting. DOACs, LMWH and warfarin have all been reported to be effective. DOACs offer fixed dosing, no monitoring requirements and fewer drug interactions, whereas long-term use of LMWH can predispose to osteoporosis which is an important concern in patients with both SCD and thalassaemic conditions. There is insufficient evidence to guide specific management of these CRTs, however, management should follow principles described in other patient groups. Our literature review identified only two studies in thalassaemia patients, Davis and Porter et al. and Miskin et al. (both presented in Table 1) who found eight out of 25 catheters were linked to catheter-associated VTE and four out of seven patients with an incidence of 0.48 and 0.41 VTE events per 1000 catheter days respectively.22, 23 This is similar to the high VTE risk seen in SCD. Since 2000, the third edition of the Thalassaemia International Federation guidelines has recommended the use of prophylactic anticoagulation in TM, as line thrombosis is relatively common.22 Risk factors identified in thalassaemia include advancing age, previous splenectomy, iron overload and long-term anaemia of <90 g/L are known risk factors for VTE in TDT and NTDT. Optimisation of both thalassaemic and non-thalassaemic risk factors is important to prevent and manage VTE. Those with previous splenectomy are reported to be at significantly increased risk for thrombosis.42 As discussed above, in the section Thromboprophylaxis in patients with SCD with CVCs, all methods of pharmaceutical anticoagulation are effective and choice can be based largely on local policy, with the caveat that long-term LMWH may increase the risk of osteoporosis in thalassaemic patients. All authors reviewed the literature and contributed equally to drafting and reviewing the manuscript. All authors contributed equally to writing, editing and reviewing the manuscript. The authors thank Antria Siakalli, from Niche Science and Technology for help in undertaking the initial literature review. The BSH General Haematology task force members at the time of writing this guideline were Dr Sara Stuart-Smith (Chair), Dr Savio Fernandes (Deputy-Chair), Dr Barbara De La Salle, Dr Suzanne Docherty, Dr Noemi Roy, Dr Jennifer Tam, Dr Nicola Ransome, Dr Jayne Parkes, Dr John Brewin and Dr Mohammed Altohami. The authors thank them, the BSH sounding board, and the BSH guidelines committee for their support in preparing this guideline. No funding sources were used in the writing of this manuscript. The BSH paid the expenses incurred during the writing of this guidance. All authors have made a declaration of interests to the BSH and Task Force Chairs which may be viewed on request. All members of the writing group have no conflicts of interest to declare. Members of the writing group will inform the writing group Chair if any new evidence becomes available that would alter the strength of the recommendations made in this document or render it obsolete. The document will be reviewed regularly by the relevant Task Force and the literature search will be re-run every 3 years to search systematically for any new evidence that may have been missed. The document will be archived and removed from the BSH current guidelines website if it becomes obsolete. If new recommendations are made an addendum will be published on the BSH guidelines website (www.b-s-h.org.uk/guidelines). While the advice and information in this guidance is believed to be true and accurate at the time of going to press, neither the authors, the BSH nor the publishers accept any legal responsibility for the content of this guidance. Searches were performed using the online search engine Medline (PubMed). Search terms were: (Sickle cell anaemia OR sickle cell anaemia OR sickle cell disease OR thalassaemia OR thalassaemia) AND (Venous catheter OR intravenous catheter OR CVC OR CVAD OR central venous access device OR portacaths OR PICC OR peripherally inserted central catheter OR intravenous catheter) AND (Venous thromboembolism OR VTE OR pulmonary embolism OR thromboembolism OR deep vein thrombosis OR catheter associated thrombosis); (Sickle cell anaemia OR sickle cell anaemia OR sickle cell disease OR thalassaemia OR thalassaemia) AND (Venous thromboembolism OR VTE OR pulmonary embolism OR thromboembolism OR deep vein thrombosis OR catheter associated thrombosis); (Sickle cell anaemia OR sickle cell disease OR thalassaemia) AND (central venous devices) AND (thrombosis OR thromboembolism); (Sickle cell anaemia OR sickle cell disease OR thalassaemia) AND (thrombosis OR thromboembolism). Filters were applied to include only publications written in English, studies carried out in humans, meta-analyses, retrospective studies, randomised controlled trials, reviews, systematic reviews, and published between 01/01/2000 and 01/04/2023. Searches of individual journals were not implemented because it was felt that publications not captured during the database search process would have had limited availability and would have had little impact on the scientific community. Titles and/or abstracts of publications obtained from the database searches described were manually reviewed and excluded if they do not adhere to the abstract review criteria. An abstract screening was performed based on the following criteria (Table A1). A literature search was initially undertaken to identify any association of venous thromboembolism with intravenous catheter devices in sickle cell anaemia and thalassaemia. Thirty-seven publications were identified and based on the abstract screening 16 articles were removed and 21 were retained. All the papers can be sent on request. These are presented in Table A2. Woods GM, Sharma R, Creary S, O'Brien S, Stanek J, Hor K, Young J, Dunn AL, Kumar R. Venous Thromboembolism in children with sickle cell disease: a retrospective cohort study. J Pediatr. 2018;197:186–90.e1. doi: 10.1016/j.jpeds.2018.01.073. Epub 2018 Mar 28. PMID: 29605397.24 Objectives: To describe the cumulative incidence of venous thromboembolism (VTE) in children with sickle cell disease (SCD) followed at a single institution and report on the risk factors associated with VTE development. Study design: Charts for all patients with SCD, aged 0–21 years, followed at Nationwide Children's Hospital over a 6-year period (January 1, 2009, to January 31, 2015) were reviewed. Data on VTE diagnosis, sex, body mass index/weight-for-length, SCD genotype, SCD clinical complications, central venous catheter (CVC) placement and thrombophilia testing were collected. Results: Cumulative incidence of VTE in children with SCD followed at a single tertiary care institution was found to be 2.9% (12/414). Nine of the 12 VTE were CVC-associated. On univariate analysis, haemoglobin SS genotype (OR 10.7, 95% CI 1.4–83.5), CVC presence (OR 34.4, 95% CI 8.9–134.6), central nervous system vasculopathy (OR 19.4, 95% CI 5.6–63.4), chronic transfusion therapy (OR 30.6, 95% CI 8.9–122.2), and older age (p = 0.03) were associated with VTE. However, presence of CVC was the only independent risk factor identified on multivariable logistic regression analysis (OR 33.8, 95% CI 8.7–130.9). Conclusion: In our institution, nearly 3% of children with SCD had a history of VTE. CVC is an independent predictor of VTE in children with SCD. Keywords: sickle cell disease; venous thromboembolism. Objective: To assess the clinical and laboratory predictors of venous thromboembolism (VTE) in patients with sickle cell anaemia (SCA) and its relationship to morbidity and mortality. Methods: This retrospective case–control study analysed data from patients with SCA that experienced VTE compared with matched control patients with SCA but no VTE (2:1 ratio). Results: A total of 102 patients with SCA were enrolled (68 cases with VTE and 34 controls). Among the 68 cases (median age, 29.5 years), 26 (38.2%) presented with isolated pulmonary embolism (PE). A higher prevalence of splenectomy (73.5% vs. 35.3%) was observed in the cases compared with the controls. A significantly higher prevalence of central venous catheter (CVC) insertion (42.6% vs. 8.8%) was observed in the cases compared with the controls. High white blood cell counts, serum lactic dehydrogenase (LDH), bilirubin and C-reactive protein (CRP) and low haemoglobin (Hb) and HbF were significant risk factors for VTE. Forty-two cases (61.8%) developed acute chest syndrome, 10 (14.7%) had a stroke and seven (10.3%) died. Conclusions: VTE in patients with SCA has a high impact on morbidity and mortality. PE was the leading presentation of VTE, with CVC insertion, high LDH, bilirubin, CRP and whi
Summary We explored transient elastography ( TE ) and enhanced liver fibrosis ( ELF ™ ) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease ( SCD ). Patients with Hb SS or HbSβ 0 thalassaemia (sickle cell anaemia, SCA ; N = 134), had significantly higher TE results and ELF scores than those with Hb SC ( N = 49) disease ( TE , 6·8 vs. 5·3, P < 0·0001 and ELF , 9·2 vs. 8·6 P < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests ( LFT s). Additionally, (weak) positive correlation was found with lactate dehydrogenase ( TE : r = 0·24, P = 0·004; ELF : r = 0·26 P = 0·002), and (weak) negative correlation with haemoglobin ( TE : r = −0·25, P = 0·002; ELF : r = −0·25 P = 0·004). In Hb SC patients, correlations were weaker or not significant between TE or ELF , and serum LFT s. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β = 0·25, P < 0·0001, total blood transfusion units, β = 0·25, P < 0·0001 and LIC β = 0·32, P = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD , needs further longitudinal studies.
HbSC disease is the second commonest form of sickle cell disease, with poorly understood pathophysiology and few treatments. We studied the role of K-Cl cotransport activity in determining clinical and laboratory features, and investigated its potential role as a biomarker. Samples were collected from 110 patients with HbSC disease and 41 with sickle cell anemia (HbSS). K-Cl cotransport activity was measured in the oxygenated (K-Cl cotransport100) and deoxygenated (K-Cl cotransport0) states, using radioactive tracer studies. K-Cl cotransport activity was high in HbSC and decreased significantly on deoxygenation. K-Cl cotransport activity correlated significantly and positively with the formation of sickle cells. On multiple regression analysis, K-Cl cotransport increased significantly and independently with increasing reticulocyte count and age. K-Cl cotransport activity was increased in patients who attended hospital with acute pain in 2011 compared to those who did not (K-Cl cotransport100: mean 3.87 versus 3.20, P=0.009, independent samples T-test; K-Cl cotransport0: mean 0.96 versus 0.68, P=0.037). On logistic regression only K-Cl cotransport was associated with hospital attendance. Increased K-Cl cotransport activity was associated with the presence of retinopathy, but this effect was confounded by age. This study links variability in a fundamental aspect of cellular pathology with a clinical outcome, suggesting that K-Cl cotransport is central to the pathology of HbSC disease. Increased K-Cl cotransport activity is associated with increasing age, which may be of pathophysiological significance. Effective inhibition of K-Cl cotransport activity is likely to be of therapeutic benefit.
Background: Acute pain is the most common complication of sickle cell disease (SCD). Patients suffering severe pain often seek treatment in an acute hospital setting. Feedback from service users indicates a lack of satisfaction with quality of care. NHS England specialised commissioning recommended forming a National Sickle Pain Group (NSPG) consisting of multi-professional stakeholders and patient representatives, to understand the range of practices and challenges in providing high-quality hospital care. Aims: The objective was to develop national guidelines for acute and chronic pain management which will improve quality of care, patient experience and outcomes. The aim was to understand the variety of acute and chronic pain management policies and protocols used across England, identify aspects of care where there was unacceptable variation and examples of good care. Methods: A questionnaire was developed through discussion meetings with members of the NSPG. This was sent to haemoglobinopathy coordinating centre (HCC) leads, to be distributed to all specialist haemoglobinopathy teams (SHTs) and local haemoglobinopathy centres (LHTs) in their network, inclusive of adult and paediatric services. Results: In total, 56 services (26 paediatric and 30 adult departments), in 39 centres completed the questionnaire (75% response rate). Of these, 51% were LHTs, 15% SHTs and 33% HCCs. The size of services varied between 0 and 808 patients for adult services and 0 and 439 patients for paediatric services. Hospital admissions with vaso-occlusive episode in the year April 2020 to March 2021 for adult services varied between 0 and 754. Admission rates in paediatric services are generally lower. For both adult and paediatric acute pain presentations, the majority of centres provided care in their hospital emergency department (ED), and only a small number offered direct access to a ward (5%) or an ambulatory facility (12%). Ambulatory facilities’ opening days ranged from 5 – 7, with 64% only operating during standard hours. Access to an acute pain service (APS) was available in 83% and 65% for adult and paediatric departments respectively. Generic pain protocols were available in 50 services. The protocols vary, but the most common analgesia prescribed in adults was morphine (oral or subcutaneous or). In children, morphine (oral or intranasal) was widely used. Individual pain protocols were used in 61% of responding centres. The NICE standard ‘<30 minutes time to first analgesia’ were not met in the majority of centres (range 30–60, outliers 80–128 min). Overall, the time to first analgesia was lower in services with ambulatory care facilities. The length of stay ranged between 3–5 days. Between 1–5% of the patients experienced a prolonged admission (>21 days). Frequent re-admissions occurred in 2–10% of the patient population (≥3 admissions/year). Education and teaching sessions were infrequently delivered for ED consultants, ED nurses, Acute Medicine consultants and pharmacists (30%, 40%, 21% and 5%). Summary: Hospital management of acute sickle pain is a significant challenge to NHS services and needs to be re-evaluated. Conclusion: The questionnaire results will inform the objectives and work plans of four working groups within the NSPG (acute pain, chronic pain, education and research). In order to develop national policies, it will be necessary to generate evidence through a more detailed audit of outcomes in scenarios of best practices identified here. No references, but a more detailed summary Summary: Hospital management of acute sickle pain is a significant challenge to NHS services and needs to be re-evaluated at local and national level. Despite publication of NICE guidelines in 2012, few services in the NHS are able to consistently provide timely pain relief. The range of policies for analgesia management is surprisingly broad. The availability of ambulatory care in some centres could function as an exemplar for national practice. There may be alternative models of care which could be effective. Patients with frequent attendance and prolonged hospital stay are present in most centres and, although relatively small as a proportion of the service, are especially challenging to manage. The management of these patients requires a multidisciplinary approach and the development of national guidance, as often this is outside the expertise of haematologists. This may be helpful in improving outcomes in this patient cohort. The infrequent delivery of teaching reveals the need for regular local and national mandatory educational training of all ED staff providing care to SCD patients during acute presentations.
A study published in 1981 examined the causes of hospital admission for a cohort of children with sickle cell disease (SCD). Since that time, the incidence and prevalence of SCD has increased markedly in the UK, and there have been many changes in the management of this disease. We undertook a study examining the causes of hospital admission of children with SCD to the same hospital as the previous study, over the 2-year period from 2008 to 2009. We found that the numbers of children being cared for by our hospital had dramatically increased over the last 50 years, but rates of hospital admission had significantly fallen (41 hospital admissions per 100 patient-years, compared with 111.3 admissions per 100 patient-years in the original study). This fall in admission rates is accounted for by 2 major components: acute painful episodes (15.7 admissions per 100 patient-years compared with 39.3 in the previous study) and admission for elective blood transfusion (0.2 admissions per 100 patient-years compared with 26.7 in the previous study). It is interesting to note that, 541 elective transfusions were carried out during the study period, but in a day-care setting rather than requiring overnight admission. This study illustrates the changes in management of SCD over the past 30 years, and reflects the overall trend common to most hospital specialties of increasing community and ambulatory care.
Liver involvement in sickle cell disease (SCD) is often referred to as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This review is based on a round-table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed, as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH.
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