AUTREV-01737; No of Pages 6 Autoimmunity Reviews xxx (2015) xxx–xxx
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Article history: Received 30 June 2015 Accepted 6 July 2015 Available online xxxx
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Keywords: Auto-immune hemolytic anemia Venous thromboembolism Pulmonary embolism Splenectomy Antiphospholipid antibodies Case–control study
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Service de Médecine Interne, Hôtel-Dieu, CHU de Nantes, 44093 Nantes, France Pôle d'Information Médicale, Evaluation et Santé Publique (PIMESP), Hôpital Saint-Jacques, CHU de Nantes, 44093 Nantes, France Faculté de Médecine, Université de Nantes, 44035 Nantes, France d Etablissement Francais du Sang Pays de Loire, 44011 Nantes, France
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M. Lecouffe-Desprets a,1, A. Néel a,1,⁎, J. Graveleau a, C. Leux b, F. Perrin a,c, B. Visomblain d, M. Artifoni a,c, A. Masseau a, J. Connault a, P. Pottier a,c, C. Agard a,c, M. Hamidou a,c
Background: The risk of venous thromboembolism (VTE) during warm autoimmune hemolytic anemia (wAIHA) is apparent in several published series. Unlike proximate disorders (autoimmune thrombocytopenia, nonimmune hemolytic diseases) little is known about the presentation and risk factors for VTE in this setting. Objective: To determine the frequency, presentation and risk factors for VTE associated with wAIHA. Methods: We performed a single center retrospective study of adult patients (N18 years) followed for wAIHA between 2009 and 2013. VTE risk factors were systematically assessed. The characteristics of patients with or without VTE were compared. VTE presentation and precipitating factors were analyzed. The Padua VTE risk score was calculated in each case. Results: Forty patients were included. wAIHA was idiopathic in 24 patients (60%). Twelve patients (30%) had Evans syndrome. Mean lowest hemoglobin level was 6.6 g/dl [3.7–11.5]. Eight patients (20%) presented VTE after the appearance of wAIHA, at a mean age of 52.5 years. All patients had pulmonary embolus, associated with a deep venous thrombosis in 4 cases. At the time of VTE 7/8 patients had frank hemolysis (median hemoglobin level: 7 g/dL) and 6/8 were outpatients with a low Padua VTE risk score. The frequency of usual VTE risk factor was similar in cases and controls. By contrast, lowest hemoglobin level was significantly lower in patients that experienced VTE (5.3 vs 7.2 g/dL, p = 0.016). During the first episode of wAIHA, patients with concurrent VTE had a more pronounced anemia (5.3 vs 7.4 g/dL, p = 0.026). At the time of VTE, anemia was more severe when no other precipitating factor was present (6 vs 8.9 g.dL, p = 0.04). Conclusion: In our cohort, 20% of patients with wAIHA presented VTE. The vast majority of VTE occurred during severe hemolytic flares and were not attributable to usual VTE risk factors. VTE prophylaxis is advisable in any patient admitted for wAIHA, irrespective of Padua VTE risk score. Prophylaxis also seems reasonable for outpatients with marked hemolysis. © 2015 Published by Elsevier B.V.
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Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study
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Contents 1. 2.
Introduction . . . . . . Methods . . . . . . . 2.1. Study population 2.2. Data collection . 2.3. Literature review 2.4. Statistical analysis
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Abbreviations: AIHA, autoimmune hemolytic anemia; APL, antiphospholipid antibodies; CLL, chronic lymphocytic leukemia; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism; wAIHA, warm autoimmune hemolytic anemia. ⁎ Corresponding author at: Service de Médecine Interne, Centre Hospitalier Universitaire de Nantes, Hôtel Dieu, 1 Place Alexis Ricordeau, 44093 NANTES, France. Tel.: +33 2 40 08 33 55; fax: +33 2 40 08 33 79. E-mail address: [email protected] (A. Néel). 1 MLD and AN equally contributed to this work as co-first authors.
http://dx.doi.org/10.1016/j.autrev.2015.07.001 1568-9972/© 2015 Published by Elsevier B.V.
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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3.
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Cohort characteristics . . . . . . . . . . . . . . . . . . 3.1.1. Clinico-biological and therapeutic features of wAIHA 3.1.2. VTE risk factors . . . . . . . . . . . . . . . . . 3.2. Frequency and presentation of VTE . . . . . . . . . . . . 3.3. Risk factors for VTE and precipitating events . . . . . . . . 3.4. Literature review . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . Autorship and disclosures . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
2.2. Data collection
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Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disorder in which auto-antibodies directed against red blood cell surface antigens induce hemolysis. The estimated incidence in adults is 0.8–3 per 105/year [1]. Autoimmune hemolytic anemia due to warm antibodies (wAIHA) accounts for 75% of all AIHAs in adults [2]. wAIHA may be secondary to various conditions such as lymphoproliferative diseases, autoimmune disorders (mainly systemic lupus erythematosus), primary immunodeficiencies, chronic viral infections, solid tumors or drugs [2]. However, wAIHA is idiopathic in 50% of cases. The increased risk of venous thromboembolism (VTE) associated with autoimmune diseases is an increasing matter of concern [3]. In AIHA, it has been suspected since the 1960s, when Allgood et al. found that pulmonary embolus (PE) was the main cause of death in their patients [4]. VTE risk has been well studied in proximate diseases such as non auto-immune hemolytic disorders [5–7] and idiopathic thrombocytopenic purpura (ITP) [8–10], in which several risk factors have been identified, such as splenectomy. By contrast, the incidence, presentation, pathogenesis and risk-factors for VTE in AIHA remains poorly delineated [11]. Interestingly, several veterinary studies performed in dogs suffering wAIHA also identified VTE as an important source of mortality and suggested a causal relationship [12–14]. The aim of our study is to analyze the frequency, presentation and risk factors for VTE in patients with wAIHA.
Eligibility criteria were verified by two investigators (JG and MLD). Chart review and anonymized data collection were performed using a standardized form (MLD). VTE presentation and risk factors were systematically recorded. The latter included personal or family history of VTE, smoking, combined oral contraceptive, menopausal hormone therapy, body mass index N 30 kg/m2 , respiratory or cardiac deficiency, venous insufficiency, splenectomy, active malignancy and antiphospholipid antibodies (APL). Biological features at diagnosis, lowest hemoglobin level during follow-up, treatment and number of relapses were recorded. Relapses were defined by the reappearance of hemolytic anemia b 10 g/dL leading to a therapeutic intervention. All patients and/or general practitioners were asked for history of VTE, including lower limb deep vein thrombosis (DVT) and pulmonary embolism (PE). Superficial vein thromboses and intra-abdominal venous thromboses (i.e. post-splenectomy portal vein thrombosis) were not studied. For patients with VTE, a triggering factor for thrombosis was searched and Padua Prediction Score Risk Assessment for VTE score was calculated, using the following baseline features: active cancer, previous VTE (with exclusion of superficial vein thrombosis), reduced mobility, already known thrombophilic condition, recent trauma or surgery, age N 70 years, heart and/or respiratory failure, acute myocardial infarction or ischemic stroke, acute infection and/or rheumatologic disorder, obesity with BMI N 30 kg/m2 and ongoing hormonal treatment [15].
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2.3. Literature review
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A Pubmed (NCBI) search was performed in order to identify case series that reported the frequency of VTE in patients with AIHA. Database search terms were “venous thromboembolism”, “pulmonary embolism”, “deep vein thrombosis”, “thrombosis”, “auto-immune hemolytic anemia” and “hemolysis”. References of all relevant articles were also checked.
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2.4. Statistical analysis
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Descriptive statistics included mean (95% confident interval) or median (range) as indicated for continuous variables and frequency (percentage) for categorical variables. Univariate analysis involved χ2 or Fischer exact test as appropriate to compare categorical variables and the nonparametric Mann–Whitney test to compare continuous variables. Significant difference was considered as P b 0.05. Data analysis was performed using the open-source R software R (Package 2.37–4) [16].
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2. Methods
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2.1. Study population
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This single-center retrospective study was performed in Nantes University Hospital (France). It has been declared to the French data protection authority (Commission Nationale Informatique et Liberté) and was approved by our local ethic committee. All patients that had a direct antiglobulin test performed at our institution between January 2009 and April 2013 were screened for inclusion in the study. The eligibility criteria were as follows: (1) diagnosis of AIHA defined by hemoglobin b 12 g/dl with features of hemolysis (low haptoglobin level) with no other cause (2) a positive IgG or IgG + C3d direct antiglobulin test (DAT) (3) age N 18 years at inclusion. Since they frequently exhibit hemorheologic abnormalities, a monoclonal IgM and a distinct clinical course, patients with cold agglutinin disease or C3d-type only positive DAT were excluded. Similarly, because of their intrinsic VTE risk and the multifactorial nature of anemia in these settings, cases presenting with solid malignancy, high-grade lymphoproliferative disease, myelodysplastic and/or myeloproliferative disorders were excluded. Patients with stage A chronic lymphocytic leukemia were not excluded.
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Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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M. Lecouffe-Desprets et al. / Autoimmunity Reviews xxx (2015) xxx–xxx t1:1 Q1 t1:2
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Table 1 Main characteristics of patients with VTE. Hb level at Platelet level at Hemolysis flare at VTE Triggering VTE (g/dl) VTE (G/l) (D:diagnosis; R: relapse) factor for VTE
t1:3 t1:4 t1:5
Gender, age at VTE (years)
AIHA type
t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13
1 2 3 4 5 6 7 8
Primary 4.1 Primary 4.7 Primary 6 Primary 6.7 Primary 7.3 Primary 8.8 Primary 8.9 Primary 12.7
M, 82 M, 60 F, 69 F, 20 M, 65 F, 59 M, 35 F, 79
194 547 365 92 404 128 264 209
+ (D) + (D) + (D) + (R) + (D) + (R) + (R) –
None None None None Acute pancreatitis None Pneumonia 8 h road trip
Risk factors for VTE
APL
Inpatient Padua Thrombotic Score prophylaxis
Respiratory insufficiency Splenectomya None Combined oral contraceptiveb BMI 30.8 kg/m2 Splenectomyc Splenectomya, active smoking None
ND Negative Negative Negative ND ND Negative ND
No No No No Yes No Yes No
2 0 0 1 5 0 4 1
No No No No No No No No
AIHA: Auto-Immune Hemolytic Anemia, APL: antiphospholipids, BMI: body mass index, Hb: hemoglobin, F: female, M: male, ND: not determined, VTE: venous thromboembolism. a 2 months earlier both. b Negative genetic thrombophilia screening c 15 years earlier.
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3. Results
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3.1. Cohort characteristics
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3.1.1. Clinico-biological and therapeutic features of wAIHA Fourty patients (27 women and 13 men) fulfilled the inclusion criteria. Their main characteristics are shown in Table 1. Mean followup duration was 6.7 years (range: 1 month – 33 years). wAIHA was idiopathic in 24 patients (60%) and secondary in 16 patients (40%). The underlying disorder was an autoimmune disease in 11 patients (systemic lupus erythematosus (n = 6), rheumatoid arthritis (n = 3), primary Sjogren's syndrome (n = 1) and auto-immune hepatitis (n = 1)), an immune deficiency in 3 patients (common immune variable deficiency (n = 1), DiGeorge syndrome (n = 1), X-linked lymphoproliferative disease (n = 1)) and stage A chronic lymphocytic leukemia in 2 patients. The median age of patients at time of diagnosis was 64.5 years [14–86]. Twelve patients (30%) had Evans syndrome, equally divided into primary and secondary wAIHA. The mean hemoglobin level at diagnosis was 7.3 g/l [3.9–12.4] and the mean lowest hemoglobin level during follow-up was 6.6 g/dl [3.7–11.5]. Mean platelet level at diagnosis was 364 G/l [77–977]. All but one patient (98%) received at least one course of corticosteroids, including intravenous steroid pulses for 7 patients. Immunosuppressive drugs and/or biologics were administered to 14 patients (35%): rituximab (8 patients, 20%), intravenous cyclophosphamide (5 patients, 12.5%), azathioprine (3 patients, 3.5%), and chlorambucil (for a patient with CLL). Splenectomy was performed in 9 patients (22.5%). Five patients (12%), mainly with Evans syndrome (4/5), received intravenous immunoglobulins. Eight patients (20%) received hydroxychloroquine for an underlying connective tissue disease.
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3.1.2. VTE risk factors Twenty-three patients (57.5%) had 1 or more VTE risk factors. Thirteen patients (32.5%) had at least 2 VTE risk factors. Venous insufficiency (15%), cardiac or respiratory insufficiency (15%) and obesity (body mass index N 30 k/m2, 15%) were the most common VTE risk factors. APL were positive in 4/18 patients (22%). None of them presented a venous thrombosis. Two patients were under long-course vitamin K antagonists for pre-existing APL syndrome. Two patients had persistent APL antibodies with no history of thrombosis or obstetrical event: low level IgG anticardiolipin (30 U. GPL, N b 10), high level IgM anticardiolipin (100 U. MPL, N b 10), IgM antiB2GP1 (56 U/ml, N b 20) and presence of lupus anticoagulant in a 48-year-old woman with SLE; low level IgG anticardiolipin (24 U. GPL, N b 10) in a 78-year-old woman with Evans syndrome and autoimmune hepatitis. Five patients were under long-course vitamin K antagonists (2 above-mentioned APL syndrome patients, 2 for mechanical heart
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In the present series, where median follow-up was 3.6 years, 8 patients (20%) presented a venous thrombotic event after the development of wAIHA. Their individual characteristics are shown in Table 1. Sex-ratio was 1 and mean age when VTE occurred was 52.5 years [20–82]. All patients had primary wAIHA and 3 patients had Evans syndrome. All patients had PE, including 3 bilateral PE, associated with a DVT in 4 patients. Seven patients (97.5%) were symptomatic with sudden onset dyspnea and hypoxemia. One patient had signs of lower limb venous thrombosis (recent onset unilateral lower limb pain and oedema), but no PE symptoms. PE was diagnosed by chest computed tomography (CT) scan in 5 cases, ventilation–perfusion scintigraphy in
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Table 2 Comparison between patients with VTE and controls.
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valve and 1 for atrial fibrillation) when wAIHA occurred, and none 201 presented a VTE event. 202
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Age at diagnosis (years) Gender (M/F) Follow-up time (years) VTE risk factors Personal history of VTE Family history of VTE Smoker Combined oral contraceptive Menopausal hormone therapy Venous insufficiency Cardiac or respiratory insufficiency BMI N 30 kg/m2 Antiphospholipids Number of risk factors AHAI characteristics Hemoglobin at diagnosis (g/dl) Minimal hemoglobin (g/dl) Platelets at diagnosis (G/l) Primary wAIHA Evans syndrome ≥1 Relapse Treatment Pulse steroids IV immunoglobulin Azathioprine Cyclosphosphamide Rituximab Splenectomy
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Patients with VTE Controls (%) (%)
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52 (14–82) 4/4 9.6 (0.5–33)
56 (14–86) 23/9 6.1 (0.08–26)
0.63 0.24 0.28
1/8 (12.5) 0/8 (0) 2/8 (25) 1/8 (12.5) 0/8 (0) 2/8 (25) 1/8 (12.5)
1/32 (3.1) 4/32 (12.5) 5/32 (15.6) 1/32 (3.1) 3/32 (9.4) 4/32 (12.5) 5/32 (15.6)
0.32 0.55 0.54 0.32 1 0.38 0.83
t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14
1/8 (15.6) 0/8 (0) 1.5 (0–4)
5/32 (15.6) 4/32 (12.5) 1 (0–4)
0.83 0.52 0.57
6.8 (3.9–10) 5.3 (3.7–7.3) 444 (366–547) 8/8 (100) 3/8 (37.5) 4/8 (50) 1/8 (12.5) 3/8 (37.5) 2/8 (25) 0/8 (0) 3/8 (37.5) 3/8 (37.5)
7.6 (5–12.4) 7.2 (5–11.5) 340 (77–977) 16/32 (50) 9/32 (28.1) 9/32 (28.1) 5/32 (15.6) 4/32 (12.5) 1/32 (3.1) 5/32 (15.6) 5/32 (15.6) 6/32 (18.8)
0.32 0.016 0.21 0.99 0.61 0.27 0.83 0.11 0.08 0.56 0.13 0.27
t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25 t2:26 t2:27 t2:28 t2:29 t2:30 t2:31
wAIHA: Warm Auto-Immune Hemolytic Anemia, BMI: body mass index, F: female, IV: t2:32 intravenous, M: male, VTE: venous thromboembolism. t2:33 Figures represent frequency (%) or median (range), otherwise indicated. t2:34
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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Comparisons of the main characteristics of patients with and without VTE are shown in Table 2. There was no significant difference between the 2 groups in terms of age, gender, idiopathic AIHA vs secondary, VTE risk factors, APL, splenectomy and treatment. The only parameter that differed among cases and controls was the lowest hemoglobin level during follow-up, which was significantly lower in patients with VTE (median: 5.3 vs 7.2 g/dL, p = 0.016). Individual data regarding precipitating events and risk factors for VTE at time of the thrombotic event are presented in Table 1. Twothirds of VTE occurred in outpatients and despite a low Padua score. All but 1 patient suffered frank uncompensated hemolysis when VTE occurred (median hemoglobin level during VTE: 7 g/dL). In 4 cases VTE was diagnosed upon admission during the first wAIHA flare. Interestingly, these patients had a more pronounced anemia as compared to those presenting with a first episode of wAIHA with no apparent VTE (Fig. 1). Among VTE events, those that occurred with no other precipitating factor than wAIHA were characterized by a more severe hemolysis as reflected by a lower hemoglobin level (Fig. 2). No relationship with steroid pulse nor intravenous immunoglobulin administration was found.
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The literature review identified 7 other series that reported on the frequency of thrombosis in patients with AIHA [4,17–22]. Five series reported detailed information regarding frequency and presentation of VTE [4,17–19,21]. Among the 212 patients included in these 5 series, 31 experienced a VTE (15%). Key findings are summarized in Table 3.
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In the 1960s, Allgood et al. identified PE as a major cause of death in their series [4]. In the last decade, VTE risk associated with AIHA has been increasingly recognized. In a recent large series of patients with an autoimmune disease in the United States, adjusted hazard ratio for VTE at 1 year was as high as 6.30 (CI 95%: 4.44–8.94) during wAIHA, whereas it was 2.13 (CI 95%: 1.89–2.40) and 4.68 (CI 95%: 4.10–5.33) for rheumatoid arthritis and systemic lupus erythematosus (SLE), respectively [23]. Several series of patients with AIHA have reported
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Fig. 2. Comparison of hemoglobin levels during venous thromboembolic events (VTE) according to the presence of a classical VTE triggering event. Horizontal bars represent the medians (p = 0.04, one-tailed Mann–Whitney test).
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on the risk of thromboembolism [17–22], but no precise data about risk factors for VTE are available. Several studies have investigated the determinant of VTE risk in immune thrombopenic purpura and nonimmune hemolytic diseases such as sickle cell disease (SCD) [7,24,25], thalassemia [26,27] or paroxysmal nocturnal hemoglobinuria (PNH) [5,6,28]. By contrast, no case–control studies have been published in wAIHA. This study is the first to systematically analyze the wide range of potential risk factors and triggering events for VTE during wAIHA. In our series, 20% of patients with warm AIHA presented VTE, which was complicated by PE in all of our patients. These finding are consistent with data from the literature: among 212 patients included in 5 previous series (Table 3), 31 experienced a VTE (15%), most of these being PE (21/31, 68%). However, we may still underestimate the risk of VTE. Indeed, PE typically occurred during a severe hemolytic flare. In such a setting, symptoms of PE (sudden onset dyspnea, hypoxemia, chest pain) may be easily attributed to anemia itself or to poor cardiac tolerance (angina pectoris, pulmonary oedema). In our series we identified 4 PE among 40 inaugural hemolysis flares. Pullakart et al. found 3 VTE events among 30 inaugural hemolysis flares [19]. These figures suggest that the prevalence of PE at the diagnosis of wAIHA could be 10%. Furthermore, it is routine practice to use thrombotic prophylaxis for inpatients with active AIHA at our center, which is concordant with the fact that most VTE occurred in outpatients in our series. Conflicting data are available in the literature about the link between VTE and APL in AIHA. A prospective study over 7 years found that 63% of patients were positive for APL [19]. An increased risk for VTE in patients with lupus anticoagulant was found, but not with anticardiolipin antibodies. However, these data are not replicated in another prospective study reported by Bongarzoni et al. [18]. In this study APL were statistically more frequent in newly diagnosed primary AIHA (47.6%) than in control subjects (4.76%). However, no VTE was recorded during the 4year follow-up. Furthermore, most of APL were transient (6/10) and no thromboembolic events were registered during the follow-up period. Roumier et al. also failed to link thrombosis to APL in their series of 60 patients [21]. In our study all 4 patients with VTE tested for APL were negative. Hence, our experience and the data in the literature do not support the hypothesis that APL could explain the occurrence of thrombosis in wAIHA. This means that the absence of APL must not let clinicians underestimate the risk of VTE. However, when APL are present, a prophylactic treatment should be discussed [29]. Several factors may contribute to the VTE risk in patients with AIHA, such as underlying disease, splenectomy or classical VTE risk factors (including age, obesity, venous insufficiency, tobacco use or cardiopulmonary comorbidities). In Allgood's cohort, who first emphasized
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2 cases and conventional thoraco–abdominal CT scan in 1 case. For half of patients (4/8), PE was concomitant with the diagnosis of wAIHA.
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M. Lecouffe-Desprets et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
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Fig. 1. Comparison of hemoglobin levels at diagnosis of wAIHA in patients with/without concurrent venous thromboembolic event (VTE). Horizontal bars represent the medians (p = 0.03, one-tailed Mann–Whitney test).
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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Venous thrombosis Allgood 1967
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Pullakart
2002
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Hendrick
2002
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Bongarzoni 2005
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Roumier
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Year
2014
Analysis
2014
Secondary Nb patients with AIHA thrombosis (type)
Splenectomy Hemolysis Comments during VTE
Retrospective (10 years) Prospective (7 years) Retrospective (16 years)
47
Warm (100%)
100%
5 (11%) (5 PE)
5/5
NS
30
NS
87%
1/8
87.5%
28
46%
0/6
100%
Prospective (4 years) Retrospective (10 years)
21
Warm (80%), mixed (10%) + cold (10%); Hb b8,5 g/dl Warm (57%) + cold (43%)
8 (27%) (7 DVT, 3 PE, 1 PT) 6 (21.4%) (5 PE, 1 DVT)
45%
None
NS
NA
60
Warm (54%) + mixed (46%)
38%
12 (20%) (8 PE, 4 PT)
NS
100%
41
Warm, associated with SLE (100%)
0
10 (24%) (NS)
NS
Arterial and venous thrombosis Kokori 1999 Retrospective (4 years)
Barcellini
Nb AIHA type patients
Retrospective (35 years)
308
100% Warm (60%), mixed (8%), cold (27%) + atypical AHAI (5%)
33 (11%) (11 PE, 13 DVT, 5 PT, 8 AT)
8/33
NS
NS
All PE occurred in splenectomized patients VTE associated with LA (p = 0.03)
AIHA associated with APL (p = 0.01) No association between VTE and APL
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AIHA associated with thrombosis (p = 0.05) and IgG ACL (p = 0.01), vs. other causes of anemia during SLE VTE associated with depth of anemia at diagnosis (p = 0.024) and splenectomy (p = 0.014), but not with APL
ACL: anticardiolipin antibodies, APL: antiphospholipids, AT: arterial thrombosis, DVT: deep vein thrombosis, Hb: hemoglobin, LA: lupus anticoagulant, PE: pulmonary embolism, PT: portal thrombosis, NA: not applicable, Nb: number, NS: not specified, SLE: systemic lupus erythematosus, VTE: venous thromboembolism.
297 298
the higher risk for VTE during AIHA, all patients with thrombotic events were splenectomized [4]. An association between splenectomy and thrombosis was found in a recent large series of 308 patients with AIHA [22]. In this study, thromboses included post-operative abdominal thrombosis due to splenectomy. Hence, the link between splenectomy and non-abdominal venous thrombosis was not assessed. The higher risk of VTE following a splenectomy is estimated between 2 and 3.5 folds, and seems to persist even 10 years after the surgery [30,31]. It seems that splenectomized patients with underlying hemolytic condition (either congenital or acquired) are at higher risk of VTE than other splenectomized patients [30,32]. In our series, 3 out of 8 patients with VTE had undergone splenectomy, which is similar to patients that did not experienced VTE. However, one may hypothesize that splenectomized patients were more frequently offered VTE prophylaxis during at risk situations. As for classical VTE risk factors, their frequency was similar among cases and controls in our study. By contrast, the only feature that differed between these 2 groups was the lowest hemoglobin level during follow-up, which was significantly lower in patients with VTE. This finding suggests that AIHA itself played a role in the occurrence of VTE. In fact, one of the striking features of VTE during wAIHA is that the overwhelming majority of VTE occurs during flares of active hemolysis. This is consistent with data from Hendrick, Pullakart and Roumier, with respectively 100%, 87.5% and 100% of VTE occurring during acute hemolysis [17,19,21]. This is also consistent with the recent finding of a large series of 308 patients, where thrombosis was more frequent in patients with deep anemia (79% in cases with Hb b 8 g/dl, p = 0.024) [22]. Furthermore, we found that patients presenting with a first hemolytic episode complicated by VTE tended to have a more severe anemia as compared to those without concurrent VTE (Fig. 1). We also found that when no other triggering factor for VTE was found, thrombosis occurred when hemoglobin was strikingly low (Fig. 2 and Table 2). This may explain why Bongarzoni et al. found no thrombosis in their study which included patients with moderate anemia (median hemoglobin: 11 g/dl), with a high proportion of cold agglutinin disease (9/21) [18]. One may speculate that VTE risk could be due to restricted mobility due to anemia rather than to hemolysis itself. However, in our series VTE due to severe wAIHA flares occurred in outpatients with no obvious mobility restriction and a low Padua risk score.
309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335
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Several veterinary studies exist on the risk of VTE during AIHA. VTE is also recognized as a major cause of death in dogs with AIHA [12,33]. Post-mortem examinations in 25 dogs with AIHA showed thromboembolism in 80% of cases [33]. In this study on 72 dogs with AIHA, severe thrombocytopenia, serum bilirubin concentration of N 5 mg/dL and hypoalbuminemia were risk factors for thromboembolism. In humans, several mechanisms may link hemolysis to thrombosis, as recently reviewed by L'Acqua and Hod [34]. Endothelial activation, enhancement of inflammation, multifactorial platelet activation and red blood cells adhesion are reported during hemolysis. Furthermore, hemolysis is characterized by reactive oxygen species generation and scavenging of nitric oxide by cell-free hemoglobin and erythrocyte arginase [34–36]. More recently, it was found that free heme triggers Neutrophil Extracellular Traps formation, which recruit red blood cells, activate platelets and promote fibrin deposition [37,38]. Our study has several limitations. As a retrospective study, biological workup was not standardized (i.e. APL screening). Furthermore, the number of patients was small because wAIHA is a rare disease. However, our cohort size compares favorably with other single center series [4, 17–20]. The small number of VTE also limits the power of statistical analyses. However, it is the first study with a systematic recording and analysis of VTE, their circumstances and risk factors in wAIHA.
336 337
5. Conclusion
358
The risk of VTE during wAIHA is significant. No classical risk factor nor APL can explain this VTE risk, which seems directly related to wAIHA. The thrombotic risk is particularly important during active hemolysis and appears to correlate with disease severity. The high frequency of PE is noteworthy and should prompt clinicians to interpret cardiopulmonary symptoms with scrutiny in this setting. VTE prophylaxis should be systematic in hospitalized patients with hemolysis flare during wAIHA, regardless of age and classical VTE risk factors, especially in splenectomized patients. The use of prophylaxis for outpatients may be discussed in light of the degree of hemolysis and associated VTE risk factors. Further studies are needed to identify very high risk patients that could better benefit from prolonged prophylaxis. Whether cold agglutinin disease carries a similar risk deserves further investigation.
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307 308
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305 306
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303 304
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301 302
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t3:14 t3:15
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Autorship and disclosures
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MLD, AN, JG and MH coordinated the research; CL and AN performed the statistical analysis; FP, BV, MA, AM, JC, PP, CA and MH contributed to and revised the manuscript; MLD and AN wrote the paper.
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Conflict of interest
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Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
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Article history: Received 30 June 2015 Accepted 6 July 2015 Available online xxxx
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Keywords: Auto-immune hemolytic anemia Venous thromboembolism Pulmonary embolism Splenectomy Antiphospholipid antibodies Case–control study
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Service de Médecine Interne, Hôtel-Dieu, CHU de Nantes, 44093 Nantes, France Pôle d'Information Médicale, Evaluation et Santé Publique (PIMESP), Hôpital Saint-Jacques, CHU de Nantes, 44093 Nantes, France Faculté de Médecine, Université de Nantes, 44035 Nantes, France d Etablissement Francais du Sang Pays de Loire, 44011 Nantes, France
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M. Lecouffe-Desprets a,1, A. Néel a,1,⁎, J. Graveleau a, C. Leux b, F. Perrin a,c, B. Visomblain d, M. Artifoni a,c, A. Masseau a, J. Connault a, P. Pottier a,c, C. Agard a,c, M. Hamidou a,c
Background: The risk of venous thromboembolism (VTE) during warm autoimmune hemolytic anemia (wAIHA) is apparent in several published series. Unlike proximate disorders (autoimmune thrombocytopenia, nonimmune hemolytic diseases) little is known about the presentation and risk factors for VTE in this setting. Objective: To determine the frequency, presentation and risk factors for VTE associated with wAIHA. Methods: We performed a single center retrospective study of adult patients (N18 years) followed for wAIHA between 2009 and 2013. VTE risk factors were systematically assessed. The characteristics of patients with or without VTE were compared. VTE presentation and precipitating factors were analyzed. The Padua VTE risk score was calculated in each case. Results: Forty patients were included. wAIHA was idiopathic in 24 patients (60%). Twelve patients (30%) had Evans syndrome. Mean lowest hemoglobin level was 6.6 g/dl [3.7–11.5]. Eight patients (20%) presented VTE after the appearance of wAIHA, at a mean age of 52.5 years. All patients had pulmonary embolus, associated with a deep venous thrombosis in 4 cases. At the time of VTE 7/8 patients had frank hemolysis (median hemoglobin level: 7 g/dL) and 6/8 were outpatients with a low Padua VTE risk score. The frequency of usual VTE risk factor was similar in cases and controls. By contrast, lowest hemoglobin level was significantly lower in patients that experienced VTE (5.3 vs 7.2 g/dL, p = 0.016). During the first episode of wAIHA, patients with concurrent VTE had a more pronounced anemia (5.3 vs 7.4 g/dL, p = 0.026). At the time of VTE, anemia was more severe when no other precipitating factor was present (6 vs 8.9 g.dL, p = 0.04). Conclusion: In our cohort, 20% of patients with wAIHA presented VTE. The vast majority of VTE occurred during severe hemolytic flares and were not attributable to usual VTE risk factors. VTE prophylaxis is advisable in any patient admitted for wAIHA, irrespective of Padua VTE risk score. Prophylaxis also seems reasonable for outpatients with marked hemolysis. © 2015 Published by Elsevier B.V.
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Introduction . . . . . . Methods . . . . . . . 2.1. Study population 2.2. Data collection . 2.3. Literature review 2.4. Statistical analysis
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Abbreviations: AIHA, autoimmune hemolytic anemia; APL, antiphospholipid antibodies; CLL, chronic lymphocytic leukemia; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism; wAIHA, warm autoimmune hemolytic anemia. ⁎ Corresponding author at: Service de Médecine Interne, Centre Hospitalier Universitaire de Nantes, Hôtel Dieu, 1 Place Alexis Ricordeau, 44093 NANTES, France. Tel.: +33 2 40 08 33 55; fax: +33 2 40 08 33 79. E-mail address: [email protected] (A. Néel). 1 MLD and AN equally contributed to this work as co-first authors.
http://dx.doi.org/10.1016/j.autrev.2015.07.001 1568-9972/© 2015 Published by Elsevier B.V.
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Cohort characteristics . . . . . . . . . . . . . . . . . . 3.1.1. Clinico-biological and therapeutic features of wAIHA 3.1.2. VTE risk factors . . . . . . . . . . . . . . . . . 3.2. Frequency and presentation of VTE . . . . . . . . . . . . 3.3. Risk factors for VTE and precipitating events . . . . . . . . 3.4. Literature review . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . Autorship and disclosures . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disorder in which auto-antibodies directed against red blood cell surface antigens induce hemolysis. The estimated incidence in adults is 0.8–3 per 105/year [1]. Autoimmune hemolytic anemia due to warm antibodies (wAIHA) accounts for 75% of all AIHAs in adults [2]. wAIHA may be secondary to various conditions such as lymphoproliferative diseases, autoimmune disorders (mainly systemic lupus erythematosus), primary immunodeficiencies, chronic viral infections, solid tumors or drugs [2]. However, wAIHA is idiopathic in 50% of cases. The increased risk of venous thromboembolism (VTE) associated with autoimmune diseases is an increasing matter of concern [3]. In AIHA, it has been suspected since the 1960s, when Allgood et al. found that pulmonary embolus (PE) was the main cause of death in their patients [4]. VTE risk has been well studied in proximate diseases such as non auto-immune hemolytic disorders [5–7] and idiopathic thrombocytopenic purpura (ITP) [8–10], in which several risk factors have been identified, such as splenectomy. By contrast, the incidence, presentation, pathogenesis and risk-factors for VTE in AIHA remains poorly delineated [11]. Interestingly, several veterinary studies performed in dogs suffering wAIHA also identified VTE as an important source of mortality and suggested a causal relationship [12–14]. The aim of our study is to analyze the frequency, presentation and risk factors for VTE in patients with wAIHA.
Eligibility criteria were verified by two investigators (JG and MLD). Chart review and anonymized data collection were performed using a standardized form (MLD). VTE presentation and risk factors were systematically recorded. The latter included personal or family history of VTE, smoking, combined oral contraceptive, menopausal hormone therapy, body mass index N 30 kg/m2 , respiratory or cardiac deficiency, venous insufficiency, splenectomy, active malignancy and antiphospholipid antibodies (APL). Biological features at diagnosis, lowest hemoglobin level during follow-up, treatment and number of relapses were recorded. Relapses were defined by the reappearance of hemolytic anemia b 10 g/dL leading to a therapeutic intervention. All patients and/or general practitioners were asked for history of VTE, including lower limb deep vein thrombosis (DVT) and pulmonary embolism (PE). Superficial vein thromboses and intra-abdominal venous thromboses (i.e. post-splenectomy portal vein thrombosis) were not studied. For patients with VTE, a triggering factor for thrombosis was searched and Padua Prediction Score Risk Assessment for VTE score was calculated, using the following baseline features: active cancer, previous VTE (with exclusion of superficial vein thrombosis), reduced mobility, already known thrombophilic condition, recent trauma or surgery, age N 70 years, heart and/or respiratory failure, acute myocardial infarction or ischemic stroke, acute infection and/or rheumatologic disorder, obesity with BMI N 30 kg/m2 and ongoing hormonal treatment [15].
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A Pubmed (NCBI) search was performed in order to identify case series that reported the frequency of VTE in patients with AIHA. Database search terms were “venous thromboembolism”, “pulmonary embolism”, “deep vein thrombosis”, “thrombosis”, “auto-immune hemolytic anemia” and “hemolysis”. References of all relevant articles were also checked.
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Descriptive statistics included mean (95% confident interval) or median (range) as indicated for continuous variables and frequency (percentage) for categorical variables. Univariate analysis involved χ2 or Fischer exact test as appropriate to compare categorical variables and the nonparametric Mann–Whitney test to compare continuous variables. Significant difference was considered as P b 0.05. Data analysis was performed using the open-source R software R (Package 2.37–4) [16].
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2.1. Study population
96
This single-center retrospective study was performed in Nantes University Hospital (France). It has been declared to the French data protection authority (Commission Nationale Informatique et Liberté) and was approved by our local ethic committee. All patients that had a direct antiglobulin test performed at our institution between January 2009 and April 2013 were screened for inclusion in the study. The eligibility criteria were as follows: (1) diagnosis of AIHA defined by hemoglobin b 12 g/dl with features of hemolysis (low haptoglobin level) with no other cause (2) a positive IgG or IgG + C3d direct antiglobulin test (DAT) (3) age N 18 years at inclusion. Since they frequently exhibit hemorheologic abnormalities, a monoclonal IgM and a distinct clinical course, patients with cold agglutinin disease or C3d-type only positive DAT were excluded. Similarly, because of their intrinsic VTE risk and the multifactorial nature of anemia in these settings, cases presenting with solid malignancy, high-grade lymphoproliferative disease, myelodysplastic and/or myeloproliferative disorders were excluded. Patients with stage A chronic lymphocytic leukemia were not excluded.
101 102 103 104 105 106 107 108 109 110 111 112 113
N
U
99 100
C
94
97 98
P
D
E
T
82 83
C
80 81
E
78 79
R
76 77
R
74 75
O
72 73
R O
70
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
114
116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139
142 143 144 145 146
149 150 151 152 153 154 155
M. Lecouffe-Desprets et al. / Autoimmunity Reviews xxx (2015) xxx–xxx t1:1 Q1 t1:2
3
Table 1 Main characteristics of patients with VTE. Hb level at Platelet level at Hemolysis flare at VTE Triggering VTE (g/dl) VTE (G/l) (D:diagnosis; R: relapse) factor for VTE
t1:3 t1:4 t1:5
Gender, age at VTE (years)
AIHA type
t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13
1 2 3 4 5 6 7 8
Primary 4.1 Primary 4.7 Primary 6 Primary 6.7 Primary 7.3 Primary 8.8 Primary 8.9 Primary 12.7
M, 82 M, 60 F, 69 F, 20 M, 65 F, 59 M, 35 F, 79
194 547 365 92 404 128 264 209
+ (D) + (D) + (D) + (R) + (D) + (R) + (R) –
None None None None Acute pancreatitis None Pneumonia 8 h road trip
Risk factors for VTE
APL
Inpatient Padua Thrombotic Score prophylaxis
Respiratory insufficiency Splenectomya None Combined oral contraceptiveb BMI 30.8 kg/m2 Splenectomyc Splenectomya, active smoking None
ND Negative Negative Negative ND ND Negative ND
No No No No Yes No Yes No
2 0 0 1 5 0 4 1
No No No No No No No No
AIHA: Auto-Immune Hemolytic Anemia, APL: antiphospholipids, BMI: body mass index, Hb: hemoglobin, F: female, M: male, ND: not determined, VTE: venous thromboembolism. a 2 months earlier both. b Negative genetic thrombophilia screening c 15 years earlier.
156
3. Results
157
3.1. Cohort characteristics
158 159
3.1.1. Clinico-biological and therapeutic features of wAIHA Fourty patients (27 women and 13 men) fulfilled the inclusion criteria. Their main characteristics are shown in Table 1. Mean followup duration was 6.7 years (range: 1 month – 33 years). wAIHA was idiopathic in 24 patients (60%) and secondary in 16 patients (40%). The underlying disorder was an autoimmune disease in 11 patients (systemic lupus erythematosus (n = 6), rheumatoid arthritis (n = 3), primary Sjogren's syndrome (n = 1) and auto-immune hepatitis (n = 1)), an immune deficiency in 3 patients (common immune variable deficiency (n = 1), DiGeorge syndrome (n = 1), X-linked lymphoproliferative disease (n = 1)) and stage A chronic lymphocytic leukemia in 2 patients. The median age of patients at time of diagnosis was 64.5 years [14–86]. Twelve patients (30%) had Evans syndrome, equally divided into primary and secondary wAIHA. The mean hemoglobin level at diagnosis was 7.3 g/l [3.9–12.4] and the mean lowest hemoglobin level during follow-up was 6.6 g/dl [3.7–11.5]. Mean platelet level at diagnosis was 364 G/l [77–977]. All but one patient (98%) received at least one course of corticosteroids, including intravenous steroid pulses for 7 patients. Immunosuppressive drugs and/or biologics were administered to 14 patients (35%): rituximab (8 patients, 20%), intravenous cyclophosphamide (5 patients, 12.5%), azathioprine (3 patients, 3.5%), and chlorambucil (for a patient with CLL). Splenectomy was performed in 9 patients (22.5%). Five patients (12%), mainly with Evans syndrome (4/5), received intravenous immunoglobulins. Eight patients (20%) received hydroxychloroquine for an underlying connective tissue disease.
172 173 174 175 176 177 178 179 180 181 182 183 184
185 186 187 Q6 188 189 190 191 192 193 194 195 196 197 198 199 200
O
3.1.2. VTE risk factors Twenty-three patients (57.5%) had 1 or more VTE risk factors. Thirteen patients (32.5%) had at least 2 VTE risk factors. Venous insufficiency (15%), cardiac or respiratory insufficiency (15%) and obesity (body mass index N 30 k/m2, 15%) were the most common VTE risk factors. APL were positive in 4/18 patients (22%). None of them presented a venous thrombosis. Two patients were under long-course vitamin K antagonists for pre-existing APL syndrome. Two patients had persistent APL antibodies with no history of thrombosis or obstetrical event: low level IgG anticardiolipin (30 U. GPL, N b 10), high level IgM anticardiolipin (100 U. MPL, N b 10), IgM antiB2GP1 (56 U/ml, N b 20) and presence of lupus anticoagulant in a 48-year-old woman with SLE; low level IgG anticardiolipin (24 U. GPL, N b 10) in a 78-year-old woman with Evans syndrome and autoimmune hepatitis. Five patients were under long-course vitamin K antagonists (2 above-mentioned APL syndrome patients, 2 for mechanical heart
R O
203
In the present series, where median follow-up was 3.6 years, 8 patients (20%) presented a venous thrombotic event after the development of wAIHA. Their individual characteristics are shown in Table 1. Sex-ratio was 1 and mean age when VTE occurred was 52.5 years [20–82]. All patients had primary wAIHA and 3 patients had Evans syndrome. All patients had PE, including 3 bilateral PE, associated with a DVT in 4 patients. Seven patients (97.5%) were symptomatic with sudden onset dyspnea and hypoxemia. One patient had signs of lower limb venous thrombosis (recent onset unilateral lower limb pain and oedema), but no PE symptoms. PE was diagnosed by chest computed tomography (CT) scan in 5 cases, ventilation–perfusion scintigraphy in
204 205
Table 2 Comparison between patients with VTE and controls.
t2:1 t2:2
D
P
3.2. Frequency and presentation of VTE
E
T
C
170 171
E
168 169
R
166 167
R
164 165
N C O
162 163
valve and 1 for atrial fibrillation) when wAIHA occurred, and none 201 presented a VTE event. 202
U
160 161
F
t1:14 t1:15 t1:16 t1:17
Age at diagnosis (years) Gender (M/F) Follow-up time (years) VTE risk factors Personal history of VTE Family history of VTE Smoker Combined oral contraceptive Menopausal hormone therapy Venous insufficiency Cardiac or respiratory insufficiency BMI N 30 kg/m2 Antiphospholipids Number of risk factors AHAI characteristics Hemoglobin at diagnosis (g/dl) Minimal hemoglobin (g/dl) Platelets at diagnosis (G/l) Primary wAIHA Evans syndrome ≥1 Relapse Treatment Pulse steroids IV immunoglobulin Azathioprine Cyclosphosphamide Rituximab Splenectomy
206 207 208 209 210 211 212 213 214
Patients with VTE Controls (%) (%)
p
t2:3
52 (14–82) 4/4 9.6 (0.5–33)
56 (14–86) 23/9 6.1 (0.08–26)
0.63 0.24 0.28
1/8 (12.5) 0/8 (0) 2/8 (25) 1/8 (12.5) 0/8 (0) 2/8 (25) 1/8 (12.5)
1/32 (3.1) 4/32 (12.5) 5/32 (15.6) 1/32 (3.1) 3/32 (9.4) 4/32 (12.5) 5/32 (15.6)
0.32 0.55 0.54 0.32 1 0.38 0.83
t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14
1/8 (15.6) 0/8 (0) 1.5 (0–4)
5/32 (15.6) 4/32 (12.5) 1 (0–4)
0.83 0.52 0.57
6.8 (3.9–10) 5.3 (3.7–7.3) 444 (366–547) 8/8 (100) 3/8 (37.5) 4/8 (50) 1/8 (12.5) 3/8 (37.5) 2/8 (25) 0/8 (0) 3/8 (37.5) 3/8 (37.5)
7.6 (5–12.4) 7.2 (5–11.5) 340 (77–977) 16/32 (50) 9/32 (28.1) 9/32 (28.1) 5/32 (15.6) 4/32 (12.5) 1/32 (3.1) 5/32 (15.6) 5/32 (15.6) 6/32 (18.8)
0.32 0.016 0.21 0.99 0.61 0.27 0.83 0.11 0.08 0.56 0.13 0.27
t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25 t2:26 t2:27 t2:28 t2:29 t2:30 t2:31
wAIHA: Warm Auto-Immune Hemolytic Anemia, BMI: body mass index, F: female, IV: t2:32 intravenous, M: male, VTE: venous thromboembolism. t2:33 Figures represent frequency (%) or median (range), otherwise indicated. t2:34
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
236 237
Comparisons of the main characteristics of patients with and without VTE are shown in Table 2. There was no significant difference between the 2 groups in terms of age, gender, idiopathic AIHA vs secondary, VTE risk factors, APL, splenectomy and treatment. The only parameter that differed among cases and controls was the lowest hemoglobin level during follow-up, which was significantly lower in patients with VTE (median: 5.3 vs 7.2 g/dL, p = 0.016). Individual data regarding precipitating events and risk factors for VTE at time of the thrombotic event are presented in Table 1. Twothirds of VTE occurred in outpatients and despite a low Padua score. All but 1 patient suffered frank uncompensated hemolysis when VTE occurred (median hemoglobin level during VTE: 7 g/dL). In 4 cases VTE was diagnosed upon admission during the first wAIHA flare. Interestingly, these patients had a more pronounced anemia as compared to those presenting with a first episode of wAIHA with no apparent VTE (Fig. 1). Among VTE events, those that occurred with no other precipitating factor than wAIHA were characterized by a more severe hemolysis as reflected by a lower hemoglobin level (Fig. 2). No relationship with steroid pulse nor intravenous immunoglobulin administration was found.
238
3.4. Literature review
239 240
243
The literature review identified 7 other series that reported on the frequency of thrombosis in patients with AIHA [4,17–22]. Five series reported detailed information regarding frequency and presentation of VTE [4,17–19,21]. Among the 212 patients included in these 5 series, 31 experienced a VTE (15%). Key findings are summarized in Table 3.
244
4. Discussion
245
In the 1960s, Allgood et al. identified PE as a major cause of death in their series [4]. In the last decade, VTE risk associated with AIHA has been increasingly recognized. In a recent large series of patients with an autoimmune disease in the United States, adjusted hazard ratio for VTE at 1 year was as high as 6.30 (CI 95%: 4.44–8.94) during wAIHA, whereas it was 2.13 (CI 95%: 1.89–2.40) and 4.68 (CI 95%: 4.10–5.33) for rheumatoid arthritis and systemic lupus erythematosus (SLE), respectively [23]. Several series of patients with AIHA have reported
241 242
246 247 248 249 250 251 252
C
234 235
E
232 233
R
230 231
R
228 229
O
226 227
C
224 225
N
222 223
U
220 221
O
218 219
Fig. 2. Comparison of hemoglobin levels during venous thromboembolic events (VTE) according to the presence of a classical VTE triggering event. Horizontal bars represent the medians (p = 0.04, one-tailed Mann–Whitney test).
R O
3.3. Risk factors for VTE and precipitating events
on the risk of thromboembolism [17–22], but no precise data about risk factors for VTE are available. Several studies have investigated the determinant of VTE risk in immune thrombopenic purpura and nonimmune hemolytic diseases such as sickle cell disease (SCD) [7,24,25], thalassemia [26,27] or paroxysmal nocturnal hemoglobinuria (PNH) [5,6,28]. By contrast, no case–control studies have been published in wAIHA. This study is the first to systematically analyze the wide range of potential risk factors and triggering events for VTE during wAIHA. In our series, 20% of patients with warm AIHA presented VTE, which was complicated by PE in all of our patients. These finding are consistent with data from the literature: among 212 patients included in 5 previous series (Table 3), 31 experienced a VTE (15%), most of these being PE (21/31, 68%). However, we may still underestimate the risk of VTE. Indeed, PE typically occurred during a severe hemolytic flare. In such a setting, symptoms of PE (sudden onset dyspnea, hypoxemia, chest pain) may be easily attributed to anemia itself or to poor cardiac tolerance (angina pectoris, pulmonary oedema). In our series we identified 4 PE among 40 inaugural hemolysis flares. Pullakart et al. found 3 VTE events among 30 inaugural hemolysis flares [19]. These figures suggest that the prevalence of PE at the diagnosis of wAIHA could be 10%. Furthermore, it is routine practice to use thrombotic prophylaxis for inpatients with active AIHA at our center, which is concordant with the fact that most VTE occurred in outpatients in our series. Conflicting data are available in the literature about the link between VTE and APL in AIHA. A prospective study over 7 years found that 63% of patients were positive for APL [19]. An increased risk for VTE in patients with lupus anticoagulant was found, but not with anticardiolipin antibodies. However, these data are not replicated in another prospective study reported by Bongarzoni et al. [18]. In this study APL were statistically more frequent in newly diagnosed primary AIHA (47.6%) than in control subjects (4.76%). However, no VTE was recorded during the 4year follow-up. Furthermore, most of APL were transient (6/10) and no thromboembolic events were registered during the follow-up period. Roumier et al. also failed to link thrombosis to APL in their series of 60 patients [21]. In our study all 4 patients with VTE tested for APL were negative. Hence, our experience and the data in the literature do not support the hypothesis that APL could explain the occurrence of thrombosis in wAIHA. This means that the absence of APL must not let clinicians underestimate the risk of VTE. However, when APL are present, a prophylactic treatment should be discussed [29]. Several factors may contribute to the VTE risk in patients with AIHA, such as underlying disease, splenectomy or classical VTE risk factors (including age, obesity, venous insufficiency, tobacco use or cardiopulmonary comorbidities). In Allgood's cohort, who first emphasized
P
217
D
2 cases and conventional thoraco–abdominal CT scan in 1 case. For half of patients (4/8), PE was concomitant with the diagnosis of wAIHA.
T
215 216
F
M. Lecouffe-Desprets et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
E
4
Fig. 1. Comparison of hemoglobin levels at diagnosis of wAIHA in patients with/without concurrent venous thromboembolic event (VTE). Horizontal bars represent the medians (p = 0.03, one-tailed Mann–Whitney test).
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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M. Lecouffe-Desprets et al. / Autoimmunity Reviews xxx (2015) xxx–xxx Table 3 AIHA and thrombosis: literature review.
t3:4 t3:5
Venous thrombosis Allgood 1967
t3:6
Pullakart
2002
t3:7
Hendrick
2002
t3:8
Bongarzoni 2005
t3:9
Roumier
t3:10 t3:11 t3:12
t3:13
Year
2014
Analysis
2014
Secondary Nb patients with AIHA thrombosis (type)
Splenectomy Hemolysis Comments during VTE
Retrospective (10 years) Prospective (7 years) Retrospective (16 years)
47
Warm (100%)
100%
5 (11%) (5 PE)
5/5
NS
30
NS
87%
1/8
87.5%
28
46%
0/6
100%
Prospective (4 years) Retrospective (10 years)
21
Warm (80%), mixed (10%) + cold (10%); Hb b8,5 g/dl Warm (57%) + cold (43%)
8 (27%) (7 DVT, 3 PE, 1 PT) 6 (21.4%) (5 PE, 1 DVT)
45%
None
NS
NA
60
Warm (54%) + mixed (46%)
38%
12 (20%) (8 PE, 4 PT)
NS
100%
41
Warm, associated with SLE (100%)
0
10 (24%) (NS)
NS
Arterial and venous thrombosis Kokori 1999 Retrospective (4 years)
Barcellini
Nb AIHA type patients
Retrospective (35 years)
308
100% Warm (60%), mixed (8%), cold (27%) + atypical AHAI (5%)
33 (11%) (11 PE, 13 DVT, 5 PT, 8 AT)
8/33
NS
NS
All PE occurred in splenectomized patients VTE associated with LA (p = 0.03)
AIHA associated with APL (p = 0.01) No association between VTE and APL
F
Author
O
t3:3
R O
t3:1 t3:2
5
AIHA associated with thrombosis (p = 0.05) and IgG ACL (p = 0.01), vs. other causes of anemia during SLE VTE associated with depth of anemia at diagnosis (p = 0.024) and splenectomy (p = 0.014), but not with APL
ACL: anticardiolipin antibodies, APL: antiphospholipids, AT: arterial thrombosis, DVT: deep vein thrombosis, Hb: hemoglobin, LA: lupus anticoagulant, PE: pulmonary embolism, PT: portal thrombosis, NA: not applicable, Nb: number, NS: not specified, SLE: systemic lupus erythematosus, VTE: venous thromboembolism.
297 298
the higher risk for VTE during AIHA, all patients with thrombotic events were splenectomized [4]. An association between splenectomy and thrombosis was found in a recent large series of 308 patients with AIHA [22]. In this study, thromboses included post-operative abdominal thrombosis due to splenectomy. Hence, the link between splenectomy and non-abdominal venous thrombosis was not assessed. The higher risk of VTE following a splenectomy is estimated between 2 and 3.5 folds, and seems to persist even 10 years after the surgery [30,31]. It seems that splenectomized patients with underlying hemolytic condition (either congenital or acquired) are at higher risk of VTE than other splenectomized patients [30,32]. In our series, 3 out of 8 patients with VTE had undergone splenectomy, which is similar to patients that did not experienced VTE. However, one may hypothesize that splenectomized patients were more frequently offered VTE prophylaxis during at risk situations. As for classical VTE risk factors, their frequency was similar among cases and controls in our study. By contrast, the only feature that differed between these 2 groups was the lowest hemoglobin level during follow-up, which was significantly lower in patients with VTE. This finding suggests that AIHA itself played a role in the occurrence of VTE. In fact, one of the striking features of VTE during wAIHA is that the overwhelming majority of VTE occurs during flares of active hemolysis. This is consistent with data from Hendrick, Pullakart and Roumier, with respectively 100%, 87.5% and 100% of VTE occurring during acute hemolysis [17,19,21]. This is also consistent with the recent finding of a large series of 308 patients, where thrombosis was more frequent in patients with deep anemia (79% in cases with Hb b 8 g/dl, p = 0.024) [22]. Furthermore, we found that patients presenting with a first hemolytic episode complicated by VTE tended to have a more severe anemia as compared to those without concurrent VTE (Fig. 1). We also found that when no other triggering factor for VTE was found, thrombosis occurred when hemoglobin was strikingly low (Fig. 2 and Table 2). This may explain why Bongarzoni et al. found no thrombosis in their study which included patients with moderate anemia (median hemoglobin: 11 g/dl), with a high proportion of cold agglutinin disease (9/21) [18]. One may speculate that VTE risk could be due to restricted mobility due to anemia rather than to hemolysis itself. However, in our series VTE due to severe wAIHA flares occurred in outpatients with no obvious mobility restriction and a low Padua risk score.
309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335
D
Several veterinary studies exist on the risk of VTE during AIHA. VTE is also recognized as a major cause of death in dogs with AIHA [12,33]. Post-mortem examinations in 25 dogs with AIHA showed thromboembolism in 80% of cases [33]. In this study on 72 dogs with AIHA, severe thrombocytopenia, serum bilirubin concentration of N 5 mg/dL and hypoalbuminemia were risk factors for thromboembolism. In humans, several mechanisms may link hemolysis to thrombosis, as recently reviewed by L'Acqua and Hod [34]. Endothelial activation, enhancement of inflammation, multifactorial platelet activation and red blood cells adhesion are reported during hemolysis. Furthermore, hemolysis is characterized by reactive oxygen species generation and scavenging of nitric oxide by cell-free hemoglobin and erythrocyte arginase [34–36]. More recently, it was found that free heme triggers Neutrophil Extracellular Traps formation, which recruit red blood cells, activate platelets and promote fibrin deposition [37,38]. Our study has several limitations. As a retrospective study, biological workup was not standardized (i.e. APL screening). Furthermore, the number of patients was small because wAIHA is a rare disease. However, our cohort size compares favorably with other single center series [4, 17–20]. The small number of VTE also limits the power of statistical analyses. However, it is the first study with a systematic recording and analysis of VTE, their circumstances and risk factors in wAIHA.
336 337
5. Conclusion
358
The risk of VTE during wAIHA is significant. No classical risk factor nor APL can explain this VTE risk, which seems directly related to wAIHA. The thrombotic risk is particularly important during active hemolysis and appears to correlate with disease severity. The high frequency of PE is noteworthy and should prompt clinicians to interpret cardiopulmonary symptoms with scrutiny in this setting. VTE prophylaxis should be systematic in hospitalized patients with hemolysis flare during wAIHA, regardless of age and classical VTE risk factors, especially in splenectomized patients. The use of prophylaxis for outpatients may be discussed in light of the degree of hemolysis and associated VTE risk factors. Further studies are needed to identify very high risk patients that could better benefit from prolonged prophylaxis. Whether cold agglutinin disease carries a similar risk deserves further investigation.
359
E
T
C
E
307 308
R
305 306
R
303 304
N C O
301 302
U
299 300
P
t3:14 t3:15
Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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Autorship and disclosures
374 375 376
MLD, AN, JG and MH coordinated the research; CL and AN performed the statistical analysis; FP, BV, MA, AM, JC, PP, CA and MH contributed to and revised the manuscript; MLD and AN wrote the paper.
377
Conflict of interest
382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421
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The authors thank Paul Milne, UK, for language editing.
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Acknowledgments
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The authors report no potential conflict of interest.
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Please cite this article as: Lecouffe-Desprets M, et al, Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.07.001
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