Thrombotic manifestations are a hallmark of many auto-immune diseases (AID), specially of warm autoimmune hemolytic anemia (wAIHA), as 15 to 33% of adults with wAIHA experience venous thromboembolic events (VTE). However, beyond the presence of positive antiphospholipid antibodies and splenectomy, risk factors for developing a VTE during wAIHA have not been clearly identified. The aim of this retrospective study was to characterize VTEs during wAIHA and to identify risk factors for VTE. Forty-eight patients with wAIHA were included, among whom 26 (54%) had secondary wAIHA. Eleven (23%) patients presented at least one VTE, that occurred during an active phase of the disease for 10/11 patients (90%). The frequency of VTE was not different between primary and secondary AIHA (23.7 vs. 19.2%; p = 0.5). The Padua prediction score based on traditional risk factors was not different between patients with and without VTE. On multivariate analysis, total bilirubin ≥ 40 μmol/L [odds ratio (OR) = 7.4; p = 0.02] and leucocyte count above 7x109/L (OR = 15.7; p = 0.02) were significantly associated with a higher risk of thrombosis. Antiphospholipid antibodies were screened in 9 out the 11 patients who presented a VTE and were negative. Thus, the frequency of VTE is high (23%) during wAIHA and VTE preferentially occur within the first weeks of diagnosis. As no clinically relevant predictive factors of VTE could be identified, the systematic use of a prophylactic anticoagulation should be recommended in case of active hemolysis and its maintenance after hospital discharge should be considered. The benefit of a systematic screening for VTE and its procedure remain to be determined.

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Introduction. Thrombotic manifestations are a hallmark of many hemolytic disorders such as sickle cell disease and paroxysmal nocturnal hemoglobinuria. However, the risk of venous thromboembolism events (VTE) associated with warm autoimmune hemolytic anemia (wAIHA) has only been investigated in few studies and reported to occur in up to 15 to 33%.1-4 Moreover, risk factors of VTE during wAIHA have not been clearly identified, except for antiphospholipid antibodies and splenectomy. The aim of this study was to characterize VTE in wAIHA and to determine predictive factors of occurrence. Methods. Medical records of patients with wAIHA taken in charge in our university hospital between March 2006 and March 2016 were retrospectively analyzed. Inclusion criteria were 1) patients older than 18, with 2) wAIHA defined as hemoglobin below 120 g/L, low haptoglobin level and a positive direct antiglobulin test (DAT) for IgG alone or with complement. Exclusion criteria were known constitutional hemolysis, negative DAT or positive DAT for complement alone, or presence of cold agglutinins. Demographic, clinical and biological characteristics of patients and treatments were recorded. All VTE were proven by ultrasound scan for deep vein thrombosis (DVT) or CT scan for pulmonary embolism (PE). Thromboses of the portal system following splenectomy were not considered. The study was approved by the ethical committee. Quantitative data are reported by median [interquartile range] and compared by Mann-Whitney test. Qualitative data are reported as percentage and compared by Khi2. p<0.05 was considered significant. Results. Forty-eight patients were included, among which 26 (54%) had a secondary wAIHA (15 lymphomas, 5 autoimmune diseases, 3 infections, 2 myeloproliferative neoplasms and 1 myelodysplastic syndrome). Median age was 65 [44-78], with 51% of female. Median hemoglobin level was 73 g/L [63-90]. Clinical and biological parameters were not significantly different between primary and secondary wAIHA, notably the frequency of VTE was similar (27.3 vs. 19.2%; p=0.5). Overall, the incidence of VTE was 22.9% (n=11): 3 patients had PE, 3 had DVT alone and 5 had both DVT and PE. Only one patient was splenectomized at the time of VTE. VTE occurred at a median time of 4 weeks [1.7-7] after the diagnosis of wAIHA, with an active hemolysis in 91% cases (10/11). The Padua score was used to quantify clinical risk factors for VTE and was not different between the two groups. The frequency of jaundice was higher in patients with VTE (44.4 vs. 7.1%; p=0.02), confirmed by a higher bilirubin level (41 [32-47.5] vs. 31 [25-39] mmol/L; p=0.04). Despite similar levels of hemoglobin (74 [56-89] vs. 72 g/L [63-89]; p=0.9), hemolysis and erythropoiesis tended to be higher in the VTE group, as the LDH level (768 [464-1254] vs. 461 UI/L [296-704]; p=0.09) and reticulocyte count (288 [147-341] vs. 158x109/L [115-249]; p=0.06) tended to be higher. Platelet count was not different between the two groups (283 [165-364] vs. 228x109/L [156-310]; p=0.5). In the VTE group, a higher leucocyte count was observed (11.9 [8.6-18.1] vs. 7.3x109/L [5.4-10.5]; p=0.02). Antiphospholipid antibodies were screened in 9/11 patients with VTE and were negative. Conclusion. A high incidence of VTE (22.9%) was observed during wAIHA. VTE preferentially occurred in the first weeks of diagnosis. As no clinically relevant predictive factors could be determined, a systematic screening for DVT at diagnosis and the use of a prophylactic anticoagulation until the hemolysis is controlled are recommended. References 1. Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients. Am J Hematol. 2014;89(9):E150-155. 2. Pullarkat V, Ngo M, Iqbal S, Espina B, Liebman HA. Detection of lupus anticoagulant identifies patients with autoimmune haemolytic anaemia at increased risk for venous thromboembolism. Br J Haematol. 2002;118(4):1166-1169. 3. Hendrick AM. Auto-immune haemolytic anaemia--a high-risk disorder for thromboembolism? Hematology. 2003;8(1):53-56. 4. Lecouffe-Desprets M, Neel A, Graveleau J, et al. Venous thromboembolism related to warm autoimmune hemolytic anemia: a case-control study. Autoimmun Rev. 2015;14(11):1023-1028. Disclosures No relevant conflicts of interest to declare.

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