Key points are not available for this paper at this time.
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 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 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
Woodward et al. (Wed,) studied this question.