Ann Hematol (2016) 95:227–232 DOI 10.1007/s00277-015-2531-8

ORIGINAL ARTICLE

Venous thromboembolism in adults with sickle cell disease: experience of a single centre in the UK V. van Hamel Parsons 1 & K Gardner 1,2 & R Patel 3 & S L Thein 1,2,4

Received: 16 February 2015 / Accepted: 13 October 2015 / Published online: 21 October 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Venous thromboembolism (VTE) is a recognised complication of sickle cell disease (SCD), long considered to be a hypercoagulable state. While there is a good understanding of arterial thrombosis in SCD, the nature of VTE in SCD is less well-characterised. In this retrospective cohort study, we found that the incidence of VTE in our patient cohort was higher than in the non-SCD black population; patients of all SCD genotypes with VTE had significantly elevated steady-state platelet counts compared to those without. Recent hospitalisation (typically with acute sickle pain) was the commonest precipitating risk factor. These findings suggest consideration of longer VTE prophylaxis for acute hospital admissions in SCD.

V. van Hamel Parsons and K Gardner contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s00277-015-2531-8) contains supplementary material, which is available to authorized users. * S L Thein [email protected]; [email protected] 1

Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK

2

Faculty of Life Sciences & Medicine, Molecular Haematology, King’s College London, London SE5 9NU, UK

3

King’s Thrombosis Centre, King’s College Hospital NHS Foundation Trust, London, UK

4

Sickle Cell Branch, National Heart, Lung, and Blood Institute, NIH, Building 10-CRC/5E-5142, 10 Center Drive, Bethesda, MD 20892, USA

Keywords Sickle cell disease . Venous thromboembolism . Deep vein thrombosis . Pulmonary embolism

Introduction Sickle cell disease (SCD) is a severe inherited blood disorder caused by the presence of haemoglobin S (HbS, α2β2S); the common genotypes include HbSS, HbSC, and HbSβ0 thalassaemia and HbSβ + thalassaemia [1]. The disease is characterised by chronic haemolytic anaemia and episodes of acute illness caused by vaso-occlusion and progressive organ damage. It is a multisystem disease underlied by a chronic inflammatory state and vasculopathy, pathological events triggered by polymerisation of the deoxygenated HbS. SCD has long been considered a hypercoagulable state [2]. Recently, a retrospective analysis of the Cooperative Study of Sickle Cell Disease (CSSCD) suggests that venous thromboembolism (VTE) is a common complication of SCD with a cumulative incidence of 11.3 % by age 40 years [3]. VTE incidence in patients with SCD is also higher than that of Factor V Leiden, a common hereditary thrombophilia. While most have found a higher prevalence than expected [4], and notably a higher prevalence of pulmonary embolism [5, 6], others have suggested that deep vein thrombosis is no more common in patients with SCD than in the wider black population [5, 6]. Although patients with SCD are subject to the same “classical” risk factors for VTE as the general population, they may also have “sickle-related complications” associated with VTE, e.g. splenectomy [7], leg ulcers [8], and pulmonary hypertension [4]. Classical risk factors are considered as either “predisposing” factors (e.g. hormonal therapy, increasing age, and genetic thrombophilias) or Bprecipitating^ factors (e.g. recent surgery or immobility). In SCD, there is increased susceptibility of both predisposing classical risk factors (e.g.

228

splenectomy) and precipitating classical risk factors, notably immobility (recurrent pain crises requiring hospitalisation) and orthopaedic surgery (risk of avascular necrosis) [9]. (See Supplementary Table 1 for a list of definitions used in the VTE literature.) We conducted a review of our large, well-defined adult sickle cohort in London, UK, to try to ascertain VTE rates, natural history, and possible risk factors.

Patients and methods The cohort included adult patients attending the Sickle Cell Centre in King’s College Hospital, London, and the study period (11 years) was between 1 January 2003 to 31 December 2013 or to the last patient record or death. The cohort included 721 patients (315 males, 406 females) with 450 HbSS, 233 HbSC, and 32 HbSβ+ thalassaemia, 5 HbSβ0 thalassaemia, and 1 HbS/HPFH genotypes. Minimum age of the patients was 18 years with a mean age of 37.0±12.4 years on the last day of the study period (31 December 2013). The distribution of patient clinic attendance in the 11-year study period was variable; median time for clinic attendance was 6 years, with an inter-quartile range 3–10 years. This gives a total of 4455 observed patient years over the 11-year study period. To identify cases, we retrospectively reviewed King’s College Hospital (KCH) electronic patient records (EPR) to look for VTE events within this 11-year period. We documented baseline laboratory values (comprising Bsteady-state^ laboratory values taken in clinic), averaged over an individual’s clinic attendance in the 11-year study period. We also documented the clinical details relating to each VTE event including risk factors, site of VTE, management, and thrombophilia screening results when performed. “Thrombophilia screening” at our institution comprises Factor V Leiden, PT20210 G/A, protein C activity, free protein S, antithrombin III, activated protein C resistance, lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein-1. Definitions of VTE were taken from NICE guidance [10] and are explained in Supplementary Table 1. It is worth noting that while an unprovoked VTE was defined as a VTE event with no preceding major clinical risk factor for VTE, it does include patients with malignancy, thrombophilia, or family history of VTE, as these represent predisposing risk factors that are persistent. Data were analysed using IBM SPSS Statistics version 22.0. Quantitative normally distributed variables are presented as mean±standard deviation and subgroups compared using two-tailed unpaired Student’s t test. Variables that were not normally distributed (C-reactive protein) were logtransformed before statistical comparison. Categorical variables were compared using a Chi-squared test.

Ann Hematol (2016) 95:227–232

Results During the 11-year study period, data were available for 721 patients, who were all of African or African-Caribbean descent. Thirty episodes of VTE were identified in 28 of the 721 patients, equivalent to a VTE incidence in the allgenotype cohort of 6.73 per 1000 patient years (30 events in total 4455 observed patient years). Among the younger adults (only those that were ≤25 years at the end of the study period), there were 9 events in 8 individuals in this young cohort of 158 individuals observed for a total of 637 years; this represents a VTE incidence of 10.99 events per 1000 patient years in SCD patients up to 25 years old. As well as analysing the Ball-genotype^ cohort, we performed sub-analysis in the different genotypic groups. For these purposes, we considered patients with HbSS or HbSβ0 thalassemia as a single subgroup of sickle cell anaemia (Table 1). Of the 28 patients who had suffered a VTE, 19 (67.9 %) had HbSS and 9 (32.1 %) HbSC; the difference was not significantly different to the overall cohort. Mean age at the time of VTE event was 33.3±12.2 years. Eight of the 28 patients (28.57 %) were ≤25 years old at the time of their first VTE event, although there was no statistical difference in age between the VTE group and wider cohort (for statistical purposes, age was taken at the end of the study period or at death if earlier). There was a preponderance of females with VTEs in the all-genotype and SCD patients (female to male 20 vs 8 and 16 vs 3, respectively), but the difference was significant only in the HbSS group. In contrast, among the HbSC patients, more male patients with VTE were identified (5 males vs 3 females), but numbers were too small for this to be statistically analysed. We also note that due to early mortality of the SCD population, this means that the large majority of women are of childbearing age (median age 34.5 years, third quartile 45.3 years). Table 2 provides details of the 30 VTE individual episodes. Of the 30 VTE episodes, 13 were isolated PE (43.33 %), 5 included both PE and DVT (16.67 %), and 12 were isolated DVT (40 %). The isolated DVT can be further divided into 8 lower limb DVT, 2 upper limb DVT (both catheter-associated), and 2 other sites of DVT (inferior vena cava and mesenteric vein thrombosis, respectively. DVT in the two patients with PE and DVT were of unspecified site. Of the 28 patients, 2 (7.1 %) had a single recurrent thromboembolic event within the study period. Twenty of the 30 VTE episodes were Bprovoked^, with the most common provoking risk factor being a recent hospital admission (15 cases); four were related to elective hospital admissions; the remainder (11/15) were emergency admissions for acute vaso-occlusive pain and other sickle-related acute complications (e.g. stroke). Of note, 7/9 VTE events in HbSC patients were isolated PE events. In 26 of the 30 episodes (86.7 %), classical risk factors for VTE were present in a

360.2±150.6 332.9±139.6 8.73±2.78 265.9±115.8 9.21±1.05 2.28±0.70 0.628±0.328

97.6±18.1

430 225 32 5 1 415.7±149.1 419.4±143.6 9.19±2.48 284.7±88.1 8.96±0.87 2.21±0.58 0.655±0.287

90.4±17.1

19 9 0 0 0

8 20

28 37.8±12.7 203 232

435 34.6±11.2

no VTE

0.056 0.001** 0.393 0.395 0.226 0.624 0.667

0.038*

432.8±143.1 389.4±123.4 9.7±2.58 320.7±104.7 9.2±0.99 2.3±0.7 0.750±0.325

89.7±14.3

0.728 between all genotypes, Not applicable 0.528 between HbSS and HbSC

0.100

0.688

p value

466.7±139.1 453.7±140.2 9.58±2.17 311.9±76.8 8.88±0.80 2.2±0.6 0.683±0.287

83.5±10.3

3 16

19 35.9±13.2

VTE

Patients with HbSS/HbSβ0

225 40.2±12.7

no VTE

0.300 0.024* 0.771 0.711 0.213 0.708 0.364

0.055

241.2±51.1 239.9±111.3 7.10±2.23 177.7±61.1 9.31±01.17 2.10±0.67 0.433±0.216

110.4±16.0

0.005** 89 136

0.627

p value

288.2±84.9 333.9±120.7 8.22±3.08 216.7±80.9 9.16±1.06 2.02±0.31 0.586±0.294

107.6±19.1

5 4

9 42.9±10.5

VTE

Sub-analysis for HbSC

0.163 0.020* 0.169 0.081 0.726 0.744 0.053

0.622

0.194

0.558

p value

**Statistically significant with p<0.01, *p<0.05. These values are in italics for visual purposes

Laboratory values represent average of all values during the 11-year study period (1 January 2003 to 31 December 2013) taken during attendance in steady-state clinics. The mean number of steady-state blood tests per patient in the study period was 9.53

362.4±150.8 336.3±140.7 8.8±2.8 266.6±114.9 9.2±1.0 2.27±0.69 0.6±0.3

Lactate dehydrogenase (IU/l) Platelet count ×109/l White blood cell count ×109/l Reticulocyte count ×109/l Mean platelet volume (fl) Ln C-reactive protein Monocyte count ×109/l

450 233 32 5 1 97.3±18.1

HbSS HbSC HbSβ+ HbSβ0 HbSHPFH

307 386

315 406

Haemoglobin (g/l)

Genotype

693 36.9±12.4

721

King’s cohort Total cohort with SCD (2003–2013) No VTE VTE

Comparison of demographic and steady-state laboratory data in the patients with and without history of VTE

Number of patients Age (years) on 31 December 2013, or on date of death, if earlier Sex Male Female

Table 1

Ann Hematol (2016) 95:227–232 229

230 Table 2

Ann Hematol (2016) 95:227–232 Clinical details of all episodes of VTE during 11-year study period

Pt no.

Age at VTE/sex

Sickle genotype

Site of VTE

Thrombophilia screen

No. of risk factors

Classical risk factors

Sickle-specific risk factors

1

16 M

HbSS

Proximal DVT

↑ Factor VIII

1

Hospitalisation (sickle crisis)

Chronic leg ulcers Chronic leg ulcers

19 M

Proximal DVT

2

2 3 4

17 F 19 F 19 F

HbSS HbSS HbSS

PE Proximal DVT Proximal DVT

Negative Not tested Lupus anticoagulant

1 1 1

5 6

19 M 20 F

HbSS HbSS

Proximal DVT PE

Not tested ↑ Factor VIII

0 1

7 8

22 F 25 F

HbSS HbSS

Proximal DVT and PE Proximal DVT and PE

Protein S deficiency Not tested

3 4

9 10 11

26 M 27 M 27 F

HbSS HbSC HbSS

DVT, type unspecified, and PE PE Proximal DVT

Not tested Protein S deficiency Negative

0 1 2

12 13 14

28 M 28 F 29 M

HbSC HbSS HbSC

Proximal DVT Proximal DVT Upper limb DVT

Negative Not tested Negative

1 1 3

15

29 F

HbSS

Upper limb DVT

Not tested

5

16

32 M

HbSC

PE

Negative

1

17

36 F

HbSS

PE

Negative

3

18 19 20

38 F 42 F 44 F

HbSC HbSS HbSS

PE DVT, type unspecified, and PE Terminal IVC

↑ Factor VIII ↑ Factor VIII Negative

1 1 3

21

45 F

HbSS

Proximal DVT and PE

Negative

3

22

45 F

HbSS

Mesenteric vein thrombosis

Not tested

4

23

49 F

HbSC

PE

Not tested

2

24 25

49 F 49 M

HbSC HbSC

PE PE

↑ Factor VIII Not tested

1 3

26

49 F

HbSS

PE

3

27

49 F

HbSS

PE

Heterozygous Factor V Leiden ↑ Factor VIII

28

50 F

HbSC

PE

↑ Factor VIII

2

51 F

PE

3

2

Family history Active infection Hospitalisation (2 weeks pre-VTE haematuria) Active infection Hospitalisation (ACS) Active infection Hospitalisation (catastrophic PPH) Immobility Active infection

Leg ulcers

Family history Hospitalisation (minor op) Immobility Previous stroke Femoral line insertion Hospitalisation (ACS) Active infection Peripheral venous line (site of clot) Central venous line (site of clot) Immobility Hospitalisation—painful crisis Active infection Obesity Long haul flight 2 days prior to VTE Active infection Immobility Hospitalisation (ACS) Pregnancy On HRT Hospitalisation (ACS, TIA) Active infection Obesity Hospitalisation (LVF) Obesity Hospitalisation Active infection Hospitalisation (painful crisis, ACS) Active infection On HRT Active infection Immobility Hospitalisation (osteomyelitis and orthopaedic surgery) Hospitalisation (THR) Immobility Obesity Hospitalisation Post-partum Obesity Malignancy (myeloma) Obesity Malignancy (myeloma)

Previous stroke Sickle nephropathy Leg ulcers

AVN

Ann Hematol (2016) 95:227–232

univariate analysis. Sickle-specific risk factors were present in 8 episodes, the most common being chronic leg ulcers present in 4 episodes (3 patients). One patient was on a regular exchange transfusion programme, and one patient was on hydroxyurea therapy preceding their VTE. It is policy at KCH to give prophylactic subcutaneous enoxaparin to all patients with SCD admitted to hospital (unless there are contraindications). Thrombophilia testing was performed in 19 of the 28 patients, of which 4 were overtly positive: 1 patient was heterozygous for Factor V Leiden, 1 was lupus anticoagulant positive, and 2 were protein S deficient. Seven further patients (25 %) had raised Factor VIII:C levels (mean 324.4 ± 71.8 IU/dl). Analysis of the steady-state laboratory values showed that the VTE cases have higher baseline platelet counts than nonVTE patients of nearly 100×109/l (p=0.001), both cohort wide and on genotype sub-analysis. Other markers of inflammation (C-reactive protein (CRP) and white blood cell count (WBC)) were not significantly different, suggestive of a noninflammatory aetiology of the increased platelet count in VTE. Total haemoglobin was also slightly but significantly lower among patients with VTE in the all-genotype group. Notably, WBC, reticulocyte count, mean platelet volume, CRP, and monocyte count were not significantly different between those with and without VTEs.

Discussion This audit demonstrates a high risk of VTE in adult patients with SCD of 6.73 per 1000 patient years. Given that the cumulative incidence of VTE increases with age, and that the mean age of the whole cohort was 36.9 years at the end of the study period, it is surprising that the incidence of VTE in this cohort is comparable to that of a non-SCD, generally older population. Among the younger adults (≤25 years), however, the VTE event rate of 10.99 per 1000 person years was much higher than expected compared with a non-SCD population [11]. In the non-SCD population of similar ethnic background (i.e. Black), VTE event rates have been documented as being 1.43 to 2.59 per 1000 patient years [12]. This provides an ethnicity-matched but not aged-matched comparison from the literature and suggests that individuals with SCD have a significantly elevated risk of VTE compared to the wider black population, but quantifying the relative risk is impossible without an age-matched comparison population. As reported in the recent retrospective study of CSSCD cohort [3], we found that the rate of PE exceeded that of isolated DVT. Previous studies have reported higher rates of PE in the black population compared to other ethnic groups, and, in particular, have pointed to a higher rate of provoked PE [13, 14]. Although we found a higher rate of PE than expected, the proportion of provoked/unprovoked events was comparable to

231

a mixed ethnicity population [15]. Very few of our patients (<1 %) have long-term venous catheters in situ, in contrast to other international centres (and there was only one DVT related to a long-term indwelling venous catheter) [4]. This retrospective study has only reported cases of overt, symptomatic VTE and may underestimate true numbers by not accounting for asymptomatic cases. In particular, acute PE is a clinically difficult diagnosis in SCD as it mimics other SCD diagnoses including acute chest syndrome (ACS), infection, and uncomplicated chest pain crisis, and diagnosis of PE in SCD can be further confounded by co-morbid chronic lung disease related to SCD. It is likely that we have underestimated VTE recurrence rate as we have only included episodes within the 11-year study period. Many of these patients have recognised traditional and/or sickle risk factors for VTE. Interestingly, higher platelet counts also appeared to be a risk factor for VTE in our patients, for all genotypes. Conversely, Btraditional^ markers (Hb, LDH, WBC, or CRP) of SCD severity were not different in the VTE cohort. Higher platelet counts have been associated with VTE in other populations; in cancer, a high baseline platelet count predicts VTE [16]. Furthermore, Mekontso et al. prospectively evaluated PE frequency in an SCD population admitted with ACS and found that the only biomarker to predict PE was admission platelet count [17]. Recent pain crisis seemed to be a common acute precipitant of VTE events in our patient cohort. While management of acute pain crisis for those admitted to hospital will have included prophylactic anticoagulation, the correlation of an elevated platelet count hints at a different underlying biology to VTE in SCD compared to other complications of SCD. Future work should address this question and, ultimately, consider whether antiplatelet agents in addition to anticoagulants should be considered in some clinical situations to reduce the risk of in VTE in SCD. Acknowledgments We thank Clive Stringer (system Delivery Manager, King’s College Hospital) for the help in the data extraction from the EPR and Robin Swabey for the help in the preparation of the manuscript. We also thank Abdel Douiri (Division of Health and Social Care Research, King’s College London, United Kingdom) for the advice on the statistical analysis. Authors’ contributions VHP and KG extracted and analysed the data. RP and SLT advised on the data analysis. All authors contributed to the writing of the manuscript. Compliance with Ethical Standards Conflict of interest The authors declare that they have no competing interests. Ethical standards The study was an audit of clinical practice. Individual patient consent was not necessary as the audit involved analysis of data which were collected as part of routine clinical care. All procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2008 (5).

232

References Rees DC, Williams TN, Gladwin MT (2010) Sickle-cell disease. Lancet 376(9757):2018–2031. doi:10.1016/S0140-6736(10) 61029-X 2. Ataga KI, Cappellini MD, Rachmilewitz EA (2007) Betathalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol 139(1):3–13 3. Naik RP, Streiff MB, Haywood C Jr, Segal JB, Lanzkron S (2014) Venous thromboembolism incidence in the cooperative study of sickle cell disease. J Thromb Haemost 12(12):2010–2016. doi:10. 1111/jth.12744 4. Naik RP, Streiff MB, Haywood C Jr, Nelson JA, Lanzkron S (2013) Venous thromboembolism in adults with sickle cell disease: a serious and under-recognized complication. Am J Med 126(5):443– 449. doi:10.1016/j.amjmed.2012.12.016 5. Stein PD, Beemath A, Meyers FA, Skaf E, Olson RE (2006) Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease. Am J Med 119(10):897.e7–11. doi: 10.1016/j.amjmed.2006.08.015 6. Novelli EM, Huynh C, Gladwin MT, Moore CG, Ragni MV (2012) Pulmonary embolism in sickle cell disease: a case-control study. J Thromb Haemost 10(5):760–766. doi:10.1111/j.1538-7836.2012. 04697.x 7. Schilling RF, Gangnon RE, Traver MI (2008) Delayed adverse vascular events after splenectomy in hereditary spherocytosis. J Thromb Haemost 6(8):1289–1295. doi:10.1111/j.1538-7836. 2008.03024.x 8. Bradbury AW, MacKenzie RK, Burns P, Fegan C (2002) Thrombophilia and chronic venous ulceration. Eur J Vasc Endovasc Surg 24(2):97–104 9. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J (2014) Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 312(10):1033–1048. doi:10.1001/jama.2014. 10517

Ann Hematol (2016) 95:227–232 10.

1.

11.

12.

13.

14.

15.

16.

17.

NICE (2012) Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Clinical guideline 144 edn. National Institute for Health and Clinical Excellence, London Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158(6):585–593 Zakai NA, Katz R, Hirsch C, Shlipak MG, Chaves PHM, Newman AB, Cushman M (2005) A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the cardiovascular health study. Arch Intern Med 165(19):2214–2220. doi:10.1001/archinte.165.19.2214 White RH, Zhou H, Murin S, Harvey D (2005) Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996. Thromb Haemost 93(2): 298–305. doi:10.1267/THRO05020298 Heit JA, Beckman MG, Bockenstedt PL, Grant AM, Key NS, Kulkarni R, Manco-Johnson MJ, Moll S, Ortel TL, Philipp CS, Network CTaHCRaP (2010) Comparison of characteristics from white- and black-americans with venous thromboembolism: a cross-sectional study. Am J Hematol 85(7):467–471. doi:10.1002/ ajh.21735 Martinez C, Cohen AT, Bamber L, Rietbrock S (2014) Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 112(2):255–263. doi:10.1160/TH13-09-0793 Simanek R, Vormittag R, Ay C, Alguel G, Dunkler D, Schwarzinger I, Steger G, Jaeger U, Zielinski C, Pabinger I (2010) High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna cancer and thrombosis study (CATS). J Thromb Haemost 8(1):114–120. doi:10. 1111/j.1538-7836.2009.03680.x Mekontso Dessap A, Deux JF, Abidi N, Lavenu-Bombled C, Melica G, Renaud B, Godeau B, Adnot S, Brochard L, BrunBuisson C, Galacteros F, Rahmouni A, Habibi A, Maitre B (2011) Pulmonary artery thrombosis during acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 184(9):1022– 1029. doi:10.1164/rccm.201105-0783OC