Clinical features and prognosis of patients with thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus: a review of 25 cases

Thrombotic thrombocytopenic purpura (TTP) is a disorder of the blood-coagulation system. It is characterized by small blood clots formed throughout the body, resulting in thrombocytopenia. The condition can result in damage to major organs or death. TTP can be divided into acute idiopathic TTP and secondary TTP, which has been seen in association with malignancy, infections, and drugs such as ticlopidine, cyclosporine, and mitomycin C [1, 2]. Although TTP in patients with systemic lupus erythematosis (SLE) is rare, TTP-SLE has high mortality, ranging from 34 to 62.5% [3, 4].

The pathogenesis of TTP-SLE is related to endothelial injury or platelet aggregation that lead to vascular injury or autoimmune response [5, 6]. Patients with TTP were found to have unusually large von Willebrand factor (VWF) multimers and thrombi that were rich in platelet aggregates [3, 7]. Subsequent studies showed that the unusually large VWF multimers were hyperactive in binding and aggregating platelets [6]. ADAMTS13 (A Disintegrin and Metalloproteinase with ThromboSpondin-1-like motifs, member 13 of this family of metalloprotease)) is an enzyme that cleaves the adhesive VWF. The lack of ADAMST13 and the formation of large multimers of VWF can trigger intravascular platelet aggregation and microthrombosis, causing the signs and symptoms of TTP [6]. In addition, excessive hemoglobin and increased thrombin and D-dimer may also contribute to the development of thrombotic microangiopathies in TTP [8].

To date, treatment options for TTP-SLE patients include plasma exchange, administration of glucocorticoids, or immunosuppressive agents. Studies reported the presence of anti-endothelial cell antibodies, anti-platelet antibodies, and anti-ADAMTS13 antibodies in TTP-SLE patients [9, 10], implicating the role of autoimmune mechanism in pathogenesis of TTP-SLE. Rituximab is a monoclonal anti-CD20 antibody, which has demonstrated effectiveness in various autoimmune hematological disorders including idiopathic TTP [11].

In this study, we retrospectively reviewed the clinical and laboratory features of 25 children diagnosed with TTP-SLE. Their clinical manifestations, treatments, and prognosis were discussed.

The diagnosis of TTP in the setting of SLE may be challenging, as the diseases have overlapping clinical symptoms such as fatigue, rash, and fever. In this retrospective study, we found the neurological symptoms (e.g. headache, conscious disturbance), gastrointestinal symptoms (e.g. vomit, abdominal pain), and urinary symptoms (e.g. edema, dark urine) favored the diagnosis of TTP-SLE. Therefore, we suggested that when new kidney and neurological symptoms arise in children with SLE, testing of LDH level and blood smear should be done to allow early diagnosis of TTP-SLE. The rate of diagnosis of TTP and SLE simultaneously appeared vary among different geographic regions. A previous study in US reported that 73% of patients had SLE diagnosed before TTP onset, whereas only 15% of patients had SLE and TTP diagnosed simultaneously [3]. In the current study, 60% of patients were diagnosed with TTP-SLE simultaneously. The incident rate was similar to those reported locally. Studies suggested that patients with TTP-SLE often had moderate to severe lupus disease activity [13], and this is in accordance with the data we observed in this study (average SLEDAI = 22.4).

The MAHA in TTP and autoimmune hemolytic anemia (AIHA) in SLE have overlapping features; however, the diseases may be differentiated through blood smear and Coombs’ test. MAHA is manifested by erythrocyte fragmentation on peripheral blood smear, whereas AIHA is characterized by the presence of autoantibodies directed toward red blood cells, usually demonstrated by a positive Coombs’ test. In our study, 17 children completed the blood smear and Coombs’ test. All of them showed erythrocyte fragmentation on blood smear, and 4 of them had positive Coombs test results. Therefore, we believed that the positive results of Coombs’ test could not completely exclude MAHA. The lacking of ADAMTS13 has been suggested as an important diagnostic test for TTP [14]. Unfortunately, only 3 patients underwent ADAMTS13 test in this study, and monitoring of the enzyme activity at regular intervals during treatment was not performed. In the future study, ADAMTS13 activity should be monitored, as it may provide helpful guidelines for treatment.

In this study, we found renal impairment occurred frequently, which was in line with the observations in adult TTP-SLE patients. In the study, it was reported that the most common type of renal pathological damage was class IV (57.7%), followed by class V (11.5%), class I (5.8%), and TMA (5.8%) [15]. Patients with severe lupus nephritis usually had TMA observed [9], and the presence of TTP can adversely affect the prognosis of the renal disease [16]. In addition, kidney TMA was usually observed in patients with severe lupus nephritis [9]. In the present study, we also found class IV and TMA the most common pathological damages observed in pediatric patients.

There has been limited consensus on the management for TTP-SLE. Although the mortality rate of the disease could reach as high as 90% if not treated properly, the survival rate has improved to 80–90% since the widespread use of plasma exchange [15]. In addition to plasma exchange, administration of glucocorticoids and immunosuppressive agent were also the treatment options for TTP-SLE. The combined therapies (plasma exchange and immunosuppressor including steroids and cytotoxic agents) were found to be more appropriate than plasma exchange or immunosuppressor alone in treating adult TTP-SLE patients and have shown to achieve a higher remission rate (65.7–90.4% vs 40–50%) [15]. In our research, a 15 years old patient with 13 SLEDAI score who had received glucocorticoid therapy combined with plasma exchange to achieve disease remission, and the number of plasma exchanges was small (4 times). While the combined therapies (plasma exchange and immunosuppressor including steroids and cytotoxic agents) were found to be more appropriate than plasma exchange or immunosuppressor alone in treating adult SLE-TTP [13]. This case suggests that for patients with older age and stable disease, we can try plasma exchange combined with glucocorticoid therapy firstly. and cyclophosphamide was given for all patients received immunosuppressive agent. On the basis of our experience, we suggested that glucocorticoids plus cyclophosphamide could effectively stabilize the SLE-TTP. However, for patients with refractory SLE-TTP, plasma exchange should be performed as soon as possible. Biologic therapy may also be used for refractory SLE-TTP.

Studies showed that rituximab could remove ADAMTS13 inhibitors and improved clinical outcomes of patients with TTP [17, 18]. In this study, the patient administrated with Rituximab showed satisfactory clinical outcome.

The current study has some limitations. First, this is a retrospective study with small sample size. Also, some laboratory and safety follow up data were missing. The results and conclusion thus may not be comprehensive. However, we believe the data reported in this study could provide useful reference for clinical practice.

Patients with TTP-SLE often had moderate to severe lupus disease activity. Testing of LDH level and blood smear should be performed when kidney and neurological symptoms arise in children with SLE, in order to allow early diagnosis of TTP-SLE. The use of combination therapy, glucocorticoids plus immunosuppressive agent, provided satisfactory clinical outcome; and patients with refractory TTP-SLE need the additional plasma exchange therapy.