Characterization of recurrent thrombosis in pediatric antiphospholipid syndrome
Authors: Maria Laura Avila, Nour Amiri, Zahra Tofighi Zavareh, Sima Abu Al‐Saoud, Christine Sabapathy, Jennifer Vincelli, Mahendranath Moharir, Earl Silverman, Suzan Williams, Leonardo R. Brandão, Deborah Levy
Journal: American Journal of Hematology (2022)

Antiphospholipid antibody syndrome (APS) is an acquired disorder defined by the presence of clinical events (arterial, venous, or small vessel thrombosis, or obstetric morbidity) and persistent detection of antiphospholipid antibodies.1 Pediatric data have shown that children with APS remain at high risk of recurrent thrombosis.2-4 Despite its frequency, recurrent thrombosis in pediatric APS remains poorly characterized. The present single-institution retrospective cohort study sought to explore the clinical features and risk factors for recurrent thrombosis in a cohort of children aged 0–18 years with definite APS, defined by the Sydney criteria.1 Patients included in the cohort were tested for both lupus anticoagulant (LAC) and IgG anticardiolipin antibodies (ACLA). The outcome was the occurrence of an objectively confirmed recurrent thrombotic event, defined as new thrombosis or documented extension of the initial event during follow-up demonstrated by an appropriate imaging technique. According to our local protocol, follow-up imaging is requested 3–6 months after diagnosis, and as per clinical indication thereafter. Characteristics of the patients, including age at the time of thrombosis, sex, type of index event (venous/arterial), the trigger of the index thrombotic event (central catheter-related yes/no), underlying condition at the time of the index thrombosis, classification of underlying disease associated with APS (SLE, autoimmune non-SLE, and non-autoimmune) and follow-up time were compared according to APS antibody profile (LAC/ACLA/both). In addition, patients with and without recurrent thrombosis were compared in terms of sex, age at the time of the index thrombotic event, trigger and type of thrombosis, APS classification, APS antibody profile, time on the therapeutic range (TTR) for patients on warfarin and the percentage of days on therapeutic low molecular weight heparin (LMWH) for patients on this group of anticoagulants, and length of follow-up. TTR (percentage of time that the INR of a patient remains in the therapeutic range), was estimated using the Rosendaal method. Both TTR and percentage of days on therapeutic LMWH were estimated up until the first recurrence in patients who had the outcome and until the end of follow-up in patients who did not have the outcome. Patients were classified as having anticoagulation refractory APS if their INR (patients on Warfarin) or anti-Xa (patients on LMWH) was on therapeutic target within a week of the documented recurrence. Pearson's Chi squared test, Fisher's exact test, and Wilcoxon rank-sum test were used for these comparisons, as appropriate. Cumulative incidence of recurrent events and recurrence-free survival time for the cohort were estimated using the Kaplan Meier estimator. Lastly, Cox proportional hazards analysis was used to explore the effect of age at the time of the index thrombotic event, sex, antibody profile, and APS-associated underlying condition on the outcome. Analyses were performed using R, Version 4.0.3. Ethics review board approval at The Hospital for Sick Children was obtained; informed consent was waived. A total of 53 children sustained their index thrombotic event between 1999 and 2020. Fifty-three percent were male (28/53). The median age at the time of the index thrombotic event was 12.5 years (25th–75th percentile 3.3–15.0 years). The median follow-up time for the cohort was 4 years (25th–75th percentile 1–8 years). We found a higher frequency of venous thrombosis as the index clinical event (40/53 events, 75%); Table S1 shows the distribution of index events. Eighteen patients (18/53, 34%) were diagnosed with SLE, 12 patients (12/53, 23%) were diagnosed with autoimmune non-SLE diseases, and the remaining patients (23/53, 43%) had non-autoimmune underlying conditions. Table S2 shows the characteristics of patients according to their antibody profile. Seventeen patients (17/53, 32%) experienced one or more recurrent thrombotic events, for a recurrence rate of 0.06 events per patient-year. The finding is in line with pediatric studies reporting a 27%–29% frequency of recurrence4-6 and with an observational study in adults describing a 34% recurrence in triple-positive patients.7 Although the heterogeneity of the different observational studies precludes a definite comparison, the risk of recurrent thrombosis in pediatric APS appears to be as high, if not higher, than in adult APS. In total, 82% (14/17 events) of the first recurrence were symptomatic (Table S3). The most common type of the first recurrence was deep vein thrombosis (7/17, 46%), followed by pulmonary embolism (4/17, 24%), both (2/17, 17%), and superficial vein thrombosis (3/17, 18%, two not related to the presence of vascular access). As shown in Figure S1, most first recurrences were seen in patients with an index thrombosis solely affecting the venous territory (15/40, 38%); all these events were also venous. Two recurrent events occurred in the 11 patients with an index arterial thrombosis (2/11, 18%); only one of these events also affected an arterial territory. Six patients sustained two recurrent events and two patients sustained three recurrent events. All these patients had venous index thrombotic events and all recurrences also affected venous territories. Only 3/10 (30%) of additional recurrences were asymptomatic (Table S3). The median time to the first recurrent event was 6 months post-index thrombosis (25th–75th percentile 3–30 months). The median time between the first and second recurrence was 86 days (25th–75th percentile 50–98 days); third recurrences occurred 5 and 46 days after the second. Therefore, the first recurrent events were documented relatively early on after the index event, and the second and third recurrent events occurred within months of the prior recurrence. The clustering of these events in time could indicate that there are periods of time throughout the course of APS when other unmeasured risk factors for thrombosis might be at play, transiently disrupting the hemostatic balance and resulting in thrombosis breakthrough events. Table S4 compares patient characteristics by recurrence. As shown in the table, although we observed that recurrent thrombosis was more frequent among children with index venous versus arterial events, we found no association between territory affected by the index thrombus and thrombosis recurrence. In addition, and similar to other pediatric reports,4, 8 patients with index arterial thrombosis in our cohort were younger than those with index venous thrombosis (median age at the time of the index event 14 years, 25th–75th percentile 9–16 years for patients presenting with venous events only, versus 4 years, 25th–75th percentile 2–13 years, for those presenting with arterial events). Hence, we found no strong indication that index arterial events are a marker of high risk for recurrence in pediatric APS, as they are in adult APS.9 This finding can be explained by the different mechanisms of disease underlying arterial events in younger patients in general and the higher frequency of additional cardiovascular risk factors for thrombosis observed in adults. Importantly, 35% of recurrent events (6/17) occurred while the patients were on documented therapeutic anticoagulation, resulting in an 11% (6/53) frequency of anticoagulant refractory APS and a rate of 0.02 anticoagulant refractory recurrent events per patient-year. The cumulative incidence of recurrent thrombosis is shown in Figure S2. The 1-year and 5-year recurrent thrombosis-free survival in the cohort was 78% (95% confidence interval [CI] 68–91%) and 68% (95% CI 55–83%), respectively. In adults with triple positivity, recurrent thrombosis-free survival estimates were slightly higher than ours, with a reported 88% 1-year and 74% 5-year event-free survival.7 We should note that our estimates, with wider CI, are less precise than those reported by Pengo et al.7 The adjusted model included age at the time of the index thrombotic event and sex. Results are shown in the Figure below (Figure 1). Holding sex constant, the risk of experiencing a recurrent event increased with age at the time of the index thrombotic event; for every year increase in age at the time of the index thrombotic event, the hazard of recurrence increased by 30% (hazard ratio 1.3, 95% CI 1.1–1.4). It could be hypothesized that the patient's age at the time of the index event might be a more accurate summary measure of several differences observed in children with APS, such as antibody profile, APS classification, underlying condition, and additional risk factors for recurrent thrombosis, and provide a better overall estimate of the risk of future recurrence in this population. There are limitations to the present study. First, the retrospective design can affect its quality. To overcome this limitation, we followed a rigorous method for data collection, where a second and a third author verified the dataset for accuracy. Second, anti-Beta 2 glycoprotein-1 antibodies were not measured in this cohort, and therefore, their role and that of the full APS antibody profile could not be investigated. In conclusion, we report a relatively large single-center cohort of 53 children with APS who were followed up for a median of 4 years. Throughout follow-up, one-third of the patients developed a recurrent thrombotic event, suggesting that pediatric APS is a high-risk condition. The risk of anticoagulation-resistant APS was similar to the risk of recurrence observed in the highest risk groups in pediatrics. Index arterial events did not carry the same risk as reported in adults, and age at the time of the index event was associated with the hazard of recurrence. Lastly, subsequent (second, third) recurrent thrombotic events generally occurred within months of each other, suggesting the importance of close follow-up of these patients. The authors declare that there is no conflict of interest. Maria Laura Avila collected data, designed the study, analyzed the data, and wrote the manuscript. Christine Sabapathy, Nour Amiri, and Zahra Tofighi Zavareh collected data, checked data accuracy, and critically reviewed the manuscript. Leonardo R. Brandão and Deborah Levy designed the study, interpreted data, and critically reviewed the manuscript. Jennifer Vincelli, Mahendranath Moharir, Earl Silverman, Sima Abu Al-Saoud, and Suzan Williams critically reviewed the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics Review Board approval was obtained prior to study initiation. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.