Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry
OBJECTIVES. The purpose of this study was to obtain data on the association of antiphospholipid antibodies with clinical manifestations in childhood and to enable future studies to determine the impact of treatment and long-term outcome of pediatric antiphospholipid syndrome.
PATIENTS AND METHODS. A European registry extended internationally of pediatric patients with antiphospholipid syndrome was established as a collaborative project of the European Antiphospholipid Antibodies Forum and Lupus Working Group of the Pediatric Rheumatology European Society. To be eligible for enrollment the patient must meet the preliminary criteria for the classification of pediatric antiphospholipid syndrome and the onset of antiphospholipid syndrome must have occurred before the patient's 18th birthday.
RESULTS. As of December 1, 2007, there were 121 confirmed antiphospholipid syndrome cases registered from 14 countries. Fifty-six patients were male, and 65 were female, with a mean age at the onset of antiphospholipid syndrome of 10.7 years. Sixty (49.5%) patients had underlying autoimmune disease. Venous thrombosis occurred in 72 (60%), arterial thrombosis in 39 (32%), small-vessel thrombosis in 7 (6%), and mixed arterial and venous thrombosis in 3 (2%). Associated nonthrombotic clinical manifestations included hematologic manifestations (38%), skin disorders (18%), and nonthrombotic neurologic manifestations (16%). Laboratory investigations revealed positive anticardiolipin antibodies in 81% of the patients, anti-β2-glycoprotein I antibodies in 67%, and lupus anticoagulant in 72%. Comparisons between different subgroups revealed that patients with primary antiphospholipid syndrome were younger and had a higher frequency of arterial thrombotic events, whereas patients with antiphospholipid syndrome associated with underlying autoimmune disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations.
CONCLUSIONS. Clinical and laboratory characterization of patients with pediatric antiphospholipid syndrome implies some important differences between antiphospholipid syndrome in pediatric and adult populations. Comparisons between children with primary antiphospholipid syndrome and antiphospholipid syndrome associated with autoimmune disease have revealed certain differences that suggest 2 distinct subgroups.
In recent years, antiphospholipid antibodies (aPLs) and their associated clinical features have been recognized increasingly in various autoimmune and nonautoimmune diseases. A close association between aPLs and recurrent arterial and/or venous thrombosis has been supported by several retrospective and prospective studies, and it seems that aPLs have a direct role in the pathogenesis of the thrombophilic state of antiphospholipid syndrome (APS).1,2 Contrasting with the extensive work on diagnosis and management of APS in adults, well-designed multicenter studies of APS in pediatric populations are very rare; consequently, there is only a little accurate information on the pediatric aspects of APS.3–5
According to the published data, there might be some important differences in the clinical spectrum of APS related to the age at onset of the disease.6,7 Several issues are unique to the pediatric population: absence of common prothrombotic risk factors present in adults, increased incidence of infection-induced aPLs, prevalence of particular disease manifestations, differences in cutoff values for determination of aPLs, and factors specific to children that affect decisions regarding long-term therapy.4 Because aPL-related thrombosis can affect any organ, pediatricians of different subspecialties must be aware of this syndrome.
The relatively low prevalence and heterogeneity of pediatric APS have hampered the scientific evaluation of currently available diagnostic and therapeutic modalities. Therefore, we established a European registry (extended internationally) of pediatric patients with APS (the Ped-APS Registry) to obtain more generalizable data on the associations of aPLs with clinical manifestations in childhood and sensitivity of aPLs in pediatric APS and to enable future studies to determine the impact of treatment and long-term outcome of pediatric APS.
The Ped-APS Registry was established in 2004 as a collaborative project of the European aPL Forum and Juvenile Systemic Lupus Erythematosus Working Group of the Pediatric Rheumatology European Society. The registry compiles data of published reports of pediatric patients with APS as well as newly diagnosed cases from all over the world. The mailing list of possible participating institutions has been provided by the Pediatric Rheumatology International Trials Organisation. In addition, we undertook a computer-assisted (PubMed, Medline, and Science Citation Index) search of the literature to locate cases of pediatric APS published in English from 1990 through 2007. The first authors of the published case reports were contacted by e-mail, regular mail, or fax, and coauthors were contacted when the first authors did not reply.
To be eligible for enrollment into the Ped-APS Registry the patient must meet the updated criteria for the classification of APS.8 These criteria were originally developed for the adult population and were adapted for the pediatric population included in our study by excluding recurrent fetal losses as one of the clinical criteria. Patients are considered as having pediatric APS if the onset of APS occurred before the patient's 18th birthday. Exclusion criteria for enrollment into the Ped-APS Registry are (1) infants born to mothers with APS and (2) infants with congenital thrombophilia. Data from the infants born to mothers with APS are collected in a separate neonatal APS registry of the European aPL Forum.9
A protocol form is used to record the clinical and laboratory characteristics of the patients. The information sought includes demographic patient characteristics, disease-related data (underlying disease, age at the onset of APS, specific site of thrombosis, associated clinical manifestations, precipitating factors), family history, laboratory features at APS diagnosis (platelet count, hemolysis, anticardiolipin antibodies [aCLs], anti-β2 glycoprotein I antibodies [anti-β2GPIs], antiprothrombin antibodies, lupus anticoagulant [LA], antinuclear antibodies [ANAs], antibodies against extractable nuclear antigens [anti-ENAs], anti–double-stranded DNA (anti-dsDNA) antibodies, complement level, and presence of inherited prothrombotic disorders), therapeutic modalities that had been prescribed after the initial aPL-related thrombotic event, and if the patients had any additional episodes of thrombosis or new clinical manifestations during follow-up. Measurement of aPLs was performed on ≥2 occasions at least 12 weeks apart by using a routine technique for detection of aPLs at each participating center. Standardized clinical and laboratory data collected into the protocol forms were transferred to a designated computerized database (Excel [Microsoft, Redmond, WA]), and deidentified information was incorporated at the official Web site of the European aPL Forum (www.med.ub.es/MIMMUN/FORUM/PEDIATRIC.HTM). The study was approved by the Slovenian Ministry of Health Ethics Committee and was performed according to the principles of the Declaration of Helsinki.
Statistical tests were performed by using subroutines from the statistical analysis package MegaStat 9.0 for MS Office (MegaStat, Butler University, Indianapolis, IN). Associations between categorical variables were tested by using the χ2 or Fischer's exact test when required. Differences were considered statistically significant at P < .05.
Twenty-four international pediatric centers from 14 countries (Argentina, Brazil, Canada, Denmark, Estonia, France, Germany, Israel, Italy, Macedonia, Serbia, Slovenia, Turkey, and United States) reported at least 1 case of pediatric APS. As of December 1, 2007, the total number of registered cases was 129. After careful review of each submitted questionnaire, we excluded 8 cases from further analysis because they did not have angiographic, imaging/Doppler, or histopathological confirmation of thrombosis (n = 2) or there was no evidence of persistently positive aCLs in medium or high titer or present anti-β2GPIs or LA (n = 6).
Among the 121 cases of confirmed pediatric APS, 41 cases had been published previously,7,10–16 and 80 cases were new. Fifty-six (46%) patients were male, and 65 (54%) patients were female, with a mean age at the onset of APS of 10.7 years (range: 1.0–17.9 years). Primary APS was present in 60 (49.5%) patients, 60 (49.5%) patients had underlying autoimmune disease, and 1 (1%) patient had underlying malignant disease (Hodgkin's lymphoma) (Table 1). Fifteen (30%) of 50 patients with systemic lupus erythematosus (SLE) or lupus-like disease were initially diagnosed as having primary APS and during the follow-up developed SLE (mean interval: 1.2 ± 1.0 years after the initial presentation as primary APS) and 11 (22%) of 50 patients developed APS at the time of SLE diagnosis.
A total of 72 (60%) patients presented with venous thrombosis, 39 (32%) with arterial thrombosis, 7 (6%) with small-vessel thrombosis, and 3 (2%) with mixed arterial and venous thrombosis. The most common initial thrombotic event was deep vein thrombosis (DVT) in the lower extremities (n = 49), followed by cerebral ischemic stroke (n = 31) and cerebral sinus vein thrombosis (n = 8) (Table 2). Precipitating factors for thrombosis were identified in 28 (23%) patients, including infectious process (n = 12), immobility related to a prolonged period of sitting or cast immobilization (n = 11), surgery (n = 3), and trauma (n = 2). Thirteen percent of the patients had positive family history for thrombosis.
Associated nonthrombotic clinical manifestations at the time of the initial thrombotic event are presented in Table 3. The most frequent associated manifestations were hematologic disorders that were present in 46 (38%) patients, followed by skin disorders in 22 (18%) patients and nonthrombotic neurologic disorders in 19 (16%) patients.
The main immunologic findings are summarized in Table 4. In the entire cohort, the presence of aCLs was detected in 81%, anti-β2GPIs in 67%, and LA in 72%. Multiple positivity of aPLs in 42 patients who were simultaneously tested for all 3 aPL subtypes is presented in Fig 1. Fourteen (33%) of these 42 patients tested positive for all 3 aPL subtypes, 20 (48%) of 42 tested positive for 2 aPL subtypes, and 8 (19%) of 42 tested positive for only 1 aPL subtype (Fig 1). Inherited prothrombotic disorders were found in 13 (45%) of 29 patients including methylentetrahydrofolate reductase C677T polymorphism (n = 6), factor V Leiden (n = 3), protein S deficiency (n = 3), protein C deficiency (n = 2), prothrombin G20210A heterozygosity (n = 1), and antithrombin deficiency (n = 1). Three patients had >1 detected hereditary thrombophilic factor. Among 16 of 29 patients who tested negative for inherited prothrombotic disorders, 7 had additional acquired prothrombotic risk factors (4 patients with autoimmune disease, 2 with immobilization, and 2 with infectious disease; 1 patient had both SLE and acute infectious disease), and 9 patients had no identifiable inherited or acquired prothrombotic risk factor other than positive aPL test results.
Differences Between Primary APS and APS Associated With Underlying Autoimmune Disease
Differences between primary APS and APS associated with underlying autoimmune disease are summarized in Table 5. In the group of patients with primary APS, the mean age at disease onset was significantly lower than in the group of patients with APS associated with autoimmune disease (P < .001). The difference in female/male ratio between patients with primary APS (29 girls vs 31 boys [ratio: 0.9:1]) and patients with APS associated with autoimmune disease (36 girls vs 24 boys [ratio: 1.5:1]) was not statistically significant (P = .2). Comparison of specific disease manifestations between the 2 groups showed a statistically significantly higher frequency of arterial thrombotic events (P = .002) and, in particular, ischemic stroke (P < .001) in the group of patients with primary APS. In contrast, patients with APS associated with autoimmune disease had a significantly higher frequency of venous thrombotic events (P = .047) and hematologic (P < .001) and skin (P = .049) disorders. Lupus nephritis was reported in 21 (35%) of 60 patients with APS associated with autoimmune disease, but only 3 (5%) of 60 patients with primary APS exhibited renal manifestations (2 patients with proteinuria > 0.5 g/day and 1 patient with hematuria). Renal biopsies in 3 patients with APS associated with autoimmune disease showed characteristic signs of renal thrombotic microangiopathy. There were no statistically significant differences in the prevalence of aPL subtypes between patients with primary APS and APS associated with autoimmune disease (Table 4). In contrast, patients with APS associated with autoimmune disease had a significantly higher prevalence of ANAs (P < .001), anti–double-stranded DNA (P < .001), and anti-ENA antibodies (P < .001) than patients with primary APS.
Treatment and Outcome
Patients were treated according to each physician's clinical judgment. All patients with venous thrombosis received long-term anticoagulation therapy. In contrast, patients with arterial thrombosis received (1) no treatment (25%), (2) antiaggregation therapy (low-dose aspirin, 3–5 mg/kg per day) (35%), or (3) anticoagulation therapy with or without concomitant antiaggregation therapy (40%). Mean follow-up time from the time of APS diagnosis and the date of inclusion into the Ped-APS Registry was 6.1 years (range: 0.7–24.7 years). Overall, 23 (19%) of 121 patients developed further APS-related thrombosis after the initial thrombotic event. Among 9 of 29 patients who were tested for inherited prothrombotic disorders and had no identifiable inherited or acquired prothrombotic risk factor other than positive aPLs, 3 (33%) of 9 patients developed recurrent thrombotic events.
Of the 23 patients with recurrent thrombosis, 14 initially had venous thrombosis, 8 had arterial thrombosis, and 1 had renal thrombotic microangiopathy. Recurrent thromboses usually occurred in a similar blood vessel type; 12 (86%) of 14 patients with initial venous thrombosis had recurrent venous events, and 6 (75%) of 8 patients with initial arterial thrombosis had recurrent arterial events. Among patients with initial arterial thrombosis, 3 of 8 with recurrent thrombotic events were receiving anticoagulation therapy, 3 were receiving antiaggregation therapy, and 2 had no treatment after the initial arterial thrombosis. Recurrence of thrombosis was slightly more common in patients with primary APS (14 of 60 patients with recurrent thrombosis) than in patients with APS associated with underlying autoimmune disease (9 of 60 patients with recurrent thrombosis), but the difference was not statistically significant (P = .2). Nine (7%) of 121 patients died during the follow-up period (2 patients with primary APS and 7 patients with APS associated with underlying disease; P = .08). The cause of death for 7 patients was thrombotic events, 1 patient died as a result of SLE complications, and 1 patient with SLE died as a result of hemophagocytic syndrome associated with splenic infarct.
The Ped-APS Registry represents the largest collection of pediatric patients with APS reported to date and provides insight to the clinical and immunologic features associated with aPLs in the pediatric population. The present data of 121 children with APS have been collected at 24 university centers and derived by different subspecialists including pediatric rheumatologists, hematologists, neurologists, and others. Only patients with thrombosis who fulfilled the criteria for definite APS, as recommended by the international consensus statement,8 were included in the cohort, thus avoiding equivocal cases and providing a representative cohort of what are currently accepted as pediatric patients with APS.
In our cohort, pediatric APS was slightly more frequent in girls than in boys (female/male ratio: 1.2:1). A slight female predominance was also found in a previous, smaller pediatric APS study,7 but in the adult APS study the female/male ratio was significantly higher, reaching 5:1.17 This difference may reflect, in part, a sampling bias, because the adult APS cohort included patients with thrombosis as well as women with recurrent fetal losses, both of which characterize consensus clinical criteria for APS in adults.8
Patients with primary APS represented 49.5% of all cases included in our cohort, which is slightly lower than in adults with primary APS reported in 53% to 57% of all patients with APS.17,18 The most common autoimmune disease associated with pediatric APS was SLE/lupus-like disease, and in 52% of these patients thrombosis occurred before or at the time of SLE diagnosis. Frequent occurrence of aPL-related thrombotic events at the time of SLE onset suggests that the inflammatory component of active SLE may additionally increase the thrombosis risk and work together with aPLs in inducing thrombosis.19–21 Moreover, it was shown recently in a large cohort of pediatric patients with SLE that the titers of aCLs and anti-β2GPIs were highest at disease presentation,22 which may provide further explanation for the high frequency of aPL-related thrombotic events observed at the onset of SLE.
Thrombotic events in patients included in the Ped-APS Registry were very diverse and included arteries and veins at any level of the vascular tree and in various organ systems. The most frequent venous thrombotic event at presentation was DVT in the lower extremities (40%), comparable with that reported from adult studies (32%).17,18 Cerebral sinus vein thrombosis (7%) was the second most common venous thrombotic event in pediatric patients with APS and was significantly more frequent than previously reported for adult patients with APS (1%).17,18 Moreover, cerebrovascular disease, including sinus vein thrombosis and ischemic stroke, was present in 32% of the pediatric patients with APS at presentation, which is higher than that reported for adults (16%–21%).17,18 In the present study, pediatric patients with APS frequently exhibited associated “nonclassical” aPL-related clinical manifestations that could not be directly attributed to the thrombotic process.23,24 Compared with the adult population,17 pediatric patients with APS exhibited a higher frequency of Evans syndrome, Raynaud phenomenon, migraine headache, and chorea.
The frequencies of aCLs and anti-β2GPIs in pediatric patients with APS were comparable to the frequencies reported from adult studies; however, pediatric patients demonstrated a higher frequency of LA than reported for adults with positive LA in 40% to 54%.17,18 Two smaller pediatric APS series also observed a high frequency of positive LA ranging from 96% to 100%.7,12 As shown in Fig 1, only 33% of our patients tested positive for all 3 aPL subtypes, and 67% of the patients tested negative for ≥1 of the aPL tests, which emphasizes the importance of routine testing for all 3 aPL subtypes in clinical practice.
Data on the presence of inherited prothrombotic disorders were available for 29 patients included in the Ped-APS Registry, and ≥1 hereditary thrombophilic risk factor was found in 45% of the tested patients. The concomitant presence of aPLs and prothrombotic gene mutations in a high percentage of children with thrombosis further supports the multifactorial pathogenesis of pediatric APS. In particular, testing for inherited prothrombotic disorders may be important for early recognition of pediatric patients with APS with highest risk for recurrent thrombosis that may benefit with intensified and prolonged anticoagulation therapy. In a study of 144 adult patients with SLE, factor V Leiden and prothrombin G20210A mutation were associated with an increased risk of venous thromboembolism and potentiated this risk when combined with aCLs and/or LA.25 The overall prevalence of inherited prothrombotic disorders in children with thrombosis ranges between 10% and 60% in different registries,26–28 and the impact of these disorders on the development of thrombosis in children with or without aPLs remains controversial.
Comparisons between pediatric patients with primary APS and APS associated with underlying autoimmune disease revealed several differences and suggest 2 distinct subgroups of pediatric APS with specific characteristics. Children with primary APS were significantly younger and had a higher frequency of arterial thrombotic events and, in particular, cerebrovascular ischemic events. In contrast, children with APS associated with underlying autoimmune disease were significantly older and had a significantly higher frequency of venous thrombotic events associated with hematologic and skin manifestations. The reason for this difference is not clear; however, it may represent a complex interplay of genetic factors, endothelial hemostatic properties, the developing coagulation and immune systems in children, and modifying factors associated with an underlying autoimmune disease such as a higher inflammatory state, circulating immunocomplexes, and cytotoxic antibodies. In particular, these findings provide further evidence that the association with autoimmune disease can modify the clinical expression of APS and that there is a need for clear distinction between manifestations related to SLE and aPL-associated manifestations.
In the present study, all patients with venous thrombosis received long-term anticoagulation therapy, and only 40% of the patients with aPL-associated arterial thrombosis received anticoagulation therapy. The low percentage of patients with arterial thrombosis who received anticoagulation therapy probably reflects controversy regarding the optimal treatment of patients with APS with arterial thrombosis, because some studies have reported no advantage of anticoagulation over antiaggregation therapy for patients with ischemic stroke.29 Overall, 19% of the pediatric patients with APS developed a recurrent thrombotic event. which is higher than reported in adult patients with APS (3%–11%)30,31 and lower than that in patients with catastrophic APS (26%).32 A recent meta-analysis of secondary thromboprophylaxis in adult patients with definite APS suggested prolonged anticoagulation at a target international normalized ratio of 2.0 to 3.0 in patients with first venous events and >3.0 for those with recurrent and/or arterial events.33 There have been no studies on the optimal management of pediatric APS, and given the high recurrence rate of thrombosis, it seems reasonable to consider anticoagulation for all pediatric patients with definite APS at least at a target international normalized ratio suggested for adult population. The 3 major precipitating factors that contributed to the development of aPL-associated thrombotic events in these children were infections, immobilization, and surgery. In our cohort, 30% of the children with SLE initially presented with primary APS and, over time, progressed into a clear-cut SLE, which is more than 4 times higher than that found in adult patients with SLE.34
The major limitation of our study was the data collection from multiple centers with different diagnostic and management characteristics. Detection of aPLs was performed by using a regular technique at each participating center, which may account for considerable interlaboratory variability.35–37 The concomitant presence of inherited prothrombotic disorders was not routinely investigated in several participating centers; therefore, accurate data on the association of pediatric APS with hereditary thrombophilia cannot be presented. Moreover, we cannot comment on the optimal level of anticoagulation therapy, because participating centers used different anticoagulation regimens, and possible adverse effects of treatment were not systematically evaluated. Another limitation of our study was the absence of classification criteria for pediatric APS, and we had to use adapted criteria for adult patients with APS. Consequently, it is possible that we excluded a subset of pediatric patients with APS who initially presented with isolated nonthrombotic manifestations and later developed thrombosis.12,38
This large international study provides insight into the clinical and immunologic manifestations of pediatric APS and identifies some important differences with APS in the adult population. Primary APS and APS associated with autoimmune disease occurred in children with similar frequency and were frequently associated with multiple aPL positivity and concomitant presence of inherited prothrombotic disorders. Children with primary APS were younger and had a higher frequency of arterial thrombotic events, whereas the children with APS associated with underlying autoimmune disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations. Our study shows that pediatric patients with APS have a very high risk of recurrent thrombotic events, but the degree of anticoagulation needed to prevent recurrent thrombotic events continues to be controversial. It is expected that periodic analysis of Ped-APS Registry data and specific focus on particular open questions will allow us to increase our knowledge of this condition and to develop consensus criteria for the classification and management of pediatric APS.
This study was supported in part by Slovenian Ministry of Higher Education, Science, and Technology grants L3-0624 and P3-0314.
We thank the following members of the European aPL Forum and the Paediatric Rheumatology European Society (PReS) who participated as investigators in this study: Sheila Knupp Feitosa de Oliveira (Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil); Susan Nielsen (Pediatric Clinic 2, State University Hospital Rigshospitalet, Copenhagen, Denmark); Chris Pruunsild (Department of General Pediatrics, Children's Clinic, Tartu University Hospitals, Tartu, Estonia); Frank Dressler (Kinderklinik, Medizinische Hochschule Hannover, Hannover, Germany); Shai Padeh (Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel); Judith Barash (Kaplan Medical Center, Rehovot, Israel); Yosef Uziel (Sapir Medical Center, Kfar Saba, Israel); Liora Harel and Masha Mukamel (Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel); Shoshana Revel-Vilk (Hadassah Hebrew University Hospital, Jerusalem, Israel); Gili Kenet (National Hemophilia Center and Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel-Hashomer, Israel); Francesco Zulian (Dipartimento di Pediatria, Universita di Padova, Padova, Italy); Fernanda Falcini (Dipartimento di Pediatria, Ospedale Meyer, Universita di Firenze, Firenze, Italy); Dafina B. Kuzmanovska (University Pediatric Clinic, Skopje, FYR Macedonia); Gordana Susic (Department of Pediatric Rheumatology, Institute of Rheumatology, Belgrade, Serbia); Atilla Buyukgebiz (Dokuz Eylul University Faculty of Medicine, Izmir, Turkey); Kanat Ozisik (Department of Cardiovascular Surgery, Ankara Numune Education and Research Hospital, Ankara, Turkey); Sevgi Gozdasoglu (Department of Pediatric Hematology, Ankara University School of Medicine, Ankara, Turkey); Vilmarie Rodriguez (Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN); and Lavjay Butani (University of California Davis Medical Center, Sacramento, CA).
- Accepted July 21, 2008.
- Address correspondence to Tadej Avčin, MD, PhD, University Children's Hospital, University Medical Center Ljubljana, Department of Allergology, Rheumatology, and Clinical Immunology, Vrazov trg 1, SI-1525 Ljubljana, Slovenia. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Well-designed multicenter studies on APS in pediatric populations are very rare; consequently, there is only a little accurate information on the pediatric aspects of APS.
What This Study Adds
We present data from a large cohort of pediatric patients with APS and report original information on clinical presentation, laboratory features, and outcomes of pediatric APS. In addition, we identify some important differences when compared with APS in adult patients.
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