Pediatric Antiphospholipid Syndrome

Transcription

1 Curr Rheumatol Rep (2015) 17: 27 DOI /s ANTIPHOSPHOLIPID SYNDROME (D ERKAN, SECTION EDITOR) Pediatric Antiphospholipid Syndrome Cassyanne L. Aguiar & Arzu Soybilgic & Tadej Avcin & Barry L. Myones Published online: 9 April 2015 # Springer Science+Business Media New York 2015 Abstract Antiphospholipid syndrome (APS) is a multisystem autoimmune condition characterized by vascular thromboses associated with persistently positive antiphospholipid antibodies. There is currently a paucity of data (incidence, prevalence, thrombosis risk, and effective treatment) in pediatric APS. The purpose of this report is to review the current literature on APS in children and neonates, identify the gaps in current knowledge, and suggest avenues for studies to fill those gaps. This article is part of the Topical Collection on Antiphospholipid Syndrome C. L. Aguiar (*) Pediatric Rheumatology, Cohen Children s Medical Center North Shore Long Island Jewish Medical Center, The Hofstra North Shore-LIJ School of Medicine, 1991 Marcus Avenue, Suite M100, Lake Success, NY 11040, USA caguiar@nshs.edu A. Soybilgic Pediatric Rheumatology, Children s Hospital of University of Illinois, 840 S. Wood St, 1206 CSB, Chicago, IL 60612, USA arzu1@uic.edu T. Avcin Department of Allergology, Rheumatology and Clinical Immunology, Children s Hospital, University Medical Center Ljubljana, Bohoriceva 20, 1525 Ljubljana, Slovenia tadej.avcin@kclj.si T. Avcin Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Bohoriceva 20, 1525 Ljubljana, Slovenia B. L. Myones Pediatric Rheumatology, 2119 Plantation Bend Drive, Sugar Land, TX 77478, USA bmyones51@gmail.com Keywords Antiphospholipid syndrome. Antiphospholipid antibodies. Pediatric. Neonatal. Catastrophic antiphospholipid syndrome. Treatment. Thrombotic risk Introduction Antiphospholipid syndrome (APS) is a multisystem autoimmune condition characterized by vascular thromboses and/or pregnancy loss associated with persistently positive antiphospholipid antibodies (apl; measured with lupus anticoagulant [LA] test, anticardiolipin antibody [acl] enzymelinked immunosorbent assay [ELISA], and/or anti-β 2 -glycoprotein-i antibody [aβ 2 GPI] ELISA) [1]. Neonatal APS manifesting with thrombotic events is a rare complication seen in infants born to mothers with apl. Pediatric APS may occur during or after the neonatal period and during childhood and adolescence due to de novo production of apl. Catastrophic APS (CAPS) has also been reported in children when there is rapid development of multiple organ thromboses and microthromboses. The purpose of this review article is to summarize what is currently known in the literature about neonatal and pediatric APS, to highlight key differences from adults, and to identify areas of needed research. Definition There are no validated criteria for diagnosing pediatric APS. The Updated Sapporo Criteria [1] might possibly be adapted for the use in the pediatric population by excluding pregnancy morbidity as one of the clinical criteria, although this currently remains to be validated (Table 1). It is important to note these classification criteria are not intended for diagnosis, in either

2 27 Page 2 of 13 Curr Rheumatol Rep (2015) 17: 27 Table 1 Adaptation of the current adult antiphospholipid syndrome classification criteria that may be useful in the pediatric population [adapted from Miyakis et al. 1] Clinical criteria Vascular thrombosis: 1 clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ confirmed objectively by validated criteria. Laboratory criteria 1. Lupus anticoagulant present in plasma, on 2 occasions at least 12 weeks apart 2. Anticardiolipin antibody of IgG and/or IgM isotype, in medium or high titer (>40 GPL or MPL, or > the 99th percentile), on 2occasions,at least 12 weeks apart. 3. Anti-β 2 -glycoprotein-i antibody of IgG and/or IgM isotype, in medium or high titer (> the 99th percentile), on 2 occasions, at least 12 weeks apart. APS is considered to be present if the clinical criterion and at least 1 of the laboratory criteria are met. These are the adult APS criteria with pregnancy morbidity omitted as not applicable to the pediatric population. These classification criteria are not intended for diagnosis but for APS research purposes (to design studies utilizing homogenous cohorts) children or adults, but for APS research purposes (to design studies utilizing homogenous cohorts) and may not be valid for the pediatric population. However, they should be used along with clinical judgment to help guide the clinician in determining whether the apl profile is Bclinically significant^ in the pediatric population. Diagnostic Considerations in Children Antiphospholipid Antibody Profile The prevalence of pediatric APS is not known due to the absence of validated criteria, standardized assays, and the lack of studies applying these assays to large cohorts of healthy children. A cohort of 61 healthy children at regular preventive visits was found to have low titers of acl IgG (11.4 %) and positive values of aβ 2 GPI IgG (3.3 %) and IgA (3.3 %) [2]. Demonstration of a Bclinically significant^ apl profile (persistent LA test and/or moderate- to high-titer apl ELISA) is critical and several considerations need to be taken into account in the pediatric population. Various environmental triggers or stressors have been suggested to induce apl production. In neonates, the stress of delivery may induce de novo apl formation [3]. Many bacterial or viral infections experienced in childhood (parvovirus B19, cytomegalovirus, varicella zoster virus, streptococcal and staphylococcal infections, mycoplasma pneumonia, and gram negativebacteria) may induce transient apl positivity via molecular mimicry [4 8]. Vaccination-induced apl may also occur particularly in the pre-school and school age child either to the infectious component or adjuvant ingredients [9, 10]. Nutritional exposures to dietary β 2 GPI may induce transient production of aβ 2 GPI in certain age groups without thrombotic events [2]. Documentation of persistent (at least 12 weeks apart) autoimmune apl is crucial for diagnostic purposes [1]. Specificity of acl and aβ 2 GPI ELISA tests for apl-related clinical events increases with higher titers. Established acl and aβ 2 GPI titer cut offs in children may be different than adults [2]. It should also be noted aβ 2 GPI found in healthy children may carry a preferential specificity for domain IV/V of β 2 GPI and are termed Binnocent antibodies,^; whereas, patients with APS mainly have antibodies directed to domain I[11]. Anti-domain I antibodies may be involved in reducing the protective effects of Annexin V, a potent anticoagulant protein, as proposed in a cross-sectional analysis of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus cohort [12]. Although not specific to pediatric patients, aβ 2 GPI IgG isotype is generally more sensitive and specific for APS compared with IgM or IgA isotype [13]. Even if IgA acl and IgA aβ 2 GPI are not part of the Updated Sapporo APS Classification Criteria, there have been recent reports of isolated IgA acl or aβ 2 GPI positivity in patients with apl-related clinical events and no other thrombosis risk factors [14, 15]. Triple apl positivity (LA, acl, and aβ 2 GPI) can be clinically more significant than double or single apl positivity [16], although this remains controversial [17]. Lupus anticoagulant test positivity is a better predictor of apl-related thrombotic events compared with other apl tests [18] and the LA test should be performed when the patient is off of anticoagulation, as both false-negative and falsepositive results can occur in anti-coagulated patients [19]. False-negative LA results may occur with acute thrombotic events or acute phase responses with elevated factor VIII, such as in inflammatory states and systemic lupus erythematosus (SLE). Thrombin time and anti-xa assays can help to identify anticoagulant effect or specific inhibitors [20]. Also, because of changes in coagulation protein levels during infant and child development [21] and difficulties in defining agespecific normal ranges of the activated partial thromboplastin time (aptt) [22], normal values for LA should be established by age group [23]. BNon-criteria^ (BNon-classical^) Manifestations of APS Non-criteria manifestations of APS include thrombocytopenia, hemolytic anemia, apl nephropathy, cardiac valve disease and neurological manifestations. They are not part of the updated classification criteria, but their presence suggest APS. In pediatrics, Bnon-criteria^ hematological, skin, and neurological non-thrombotic manifestations are also seen. There is a high percentage of patients with Evans Syndrome, cytopenias, livedo reticularis, Raynaud phenomenon, migraine headache, and chorea [24 ]. Cognitive impairment with inattention or memory loss due to APS in the pediatric

3 Curr Rheumatol Rep (2015) 17: 27 Page 3 of age group can be particularly difficult to distinguish from nonorganic learning disabilities [25]. Clinical Spectrum of apl/aps It is important to always keep in mind that clinical manifestations related to apl positivity represent a spectrum: apl positivity without clinical events, apl positivity with nonthrombotic manifestations (e.g., thrombocytopenia, hemolytic anemia, and neurological manifestations), APS based on vascular thrombosis and catastrophic APS. Neonatal APS: How Is APS Different in Newborns? Coagulation System in Newborns Developmental hemostasis in newborns and children is what may be the underlying differences of childhood versus adult APS [26]. Newborns represent the largest childhood group to develop thromboembolic events, due in large part to developmentally inherent hemostatic differences [21]. In the newborn period, there is decreased thrombin-plasminogen, decreased coagulation factors, decreased platelet aggregation, decreased protein C, protein S, anti-thrombin III, and relative vitamin K deficiency [21]. Along with congenital or inherited (factor and/or protein deficiencies and/or gene mutations) and perinatal acquired (arterial and/or venous access devices) risk factors, these combine to contribute to a thrombosis risk higher than any other childhood age group [27]. In the second year and until puberty, coagulation factor concentrations change and favor an anticoagulant milieu. Children Born to Mothers with APS (Neonatal APS from Mothers with APS) Thrombosis in infants born to mothers with APS is rare, in spite of an approximately 30 % transplacental rate of passage of apl [28]. This may be explained by apl IgG subclasses having a different capacity to cross the placenta. The most efficiently transferred subclass across the placenta is IgG1 followed by IgG4 with IgG3 and IgG2 being the least efficiently transferred [29, 30]. In adult APS, IgG3 and, especially, IgG2 have been noted to be significantly associated with vascular thromboses and fetal loss with the IgG2 subclass being the most predominant and pathogenic [13, 31, 32]. Sixteen cases of infants with perinatal (pre- and post-partum injury) thrombosis born to mothers with apl were retrospectively reviewed across a 20-year span [33]. Thrombosis were mostly arterial events (13/16) with half being stroke lesions suggestive of intrauterine thromboembolism originating from the placenta. Seventy-five percent (12/16) of infants had apl present at birth or during the neonatal period with 11/12 having the same apl isotype as their mother suggesting a mechanism of transplacental transfer. Risk factors additional to apl [preeclampsia, intrauterine growth restriction, asphyxia, sepsis, arterial or venous catheter, and congenital thrombophilia] were present in 9/14. The presence of apl as the only risk factor was seen in 5/14 full-term babies and these mostly belonged to a group of mothers that were not treated with aspirin and/or heparin during pregnancy because apl status was unknown (discovered after the infants thrombotic event) suggesting an additional risk factor being untreated women with unknown apl status or women with known APS not treated with heparin. More recently, an updated review of 21 neonates from the last 27 years, including patients from the prior review, found acl to be predominant (13/21) in the apl profiles [34]. One cohort of infants born to apl positive mothers prospectively followed for apl over 1 year were found to have negative acl by 12 months of age compared to age matched control groups, whereas aβ 2 GPI persisted in all groups likely due to nonspecific factors. This suggested acl may be better to assess disappearance of maternal apl and estimate potential risks of thrombosis [28]. Study limitations include the small number of infants in each group ( 20) and follow-up only until 12 months of age. Specific details were not provided on maternal treatments during pregnancy or the neurodevelopmental testing used to assess neurological outcomes. APS Babies Registry The European Registry of babies born to mothers with apl was initiated in 2003 by the European apl Forum. It aimed to describe the long-term outcomes and immunological status of children born to mothers with APS, determine the factors responsible for childhood abnormalities, and correlate the child s immunological profile with their mothers [35, 36]. The APS babies registry included all consecutive newborns of all mothers who had thrombotic and/or obstetric APS according to Sapporo criteria. The cut offs used in maternal diagnosis (medium titer 99th %) were 20 UGPL for IgG and 20 UMPL for IgM acl as well as 15 U/ml for IgG and IgM aβ 2 GPI [37]. Seven obstetric centers participated to follow children from birth up to 5 years of age [38 ]. As of 2013, 134 babies have been included and prospectively reported on [38 ]. No neonate has developed thrombosis or SLE. Long-Term Outcomes of Children Born to Mothers with APS There is much interest in the long-term behavior and neuropsychological outcome of offspring of mothers with autoimmune disease [39]. Offspring of mothers with SLE having a flare could have more dyslexia and learning disabilities related to anti-ro and anti-la during pregnancy [40]. Offspring of mothers with APS showed learning disabilities in % of cases in two retrospective reports [41, 42]. These findings

4 27 Page 4 of 13 Curr Rheumatol Rep (2015) 17: 27 need further confirmation in prospective studies, since one published study had no control groups and very small (less than 20) sample size and the other was a case control study with retrospective data collection and prospective follow-up. The multicenter APS babies registry, although limited by 80 % of subjects lost to follow-up by the 5-year mark (n=27), found four children displaying behavioral abnormalities (autism, hyperactive behavior, language delay, and psychomotor delay with axial hypotony) [38 ]. All 4 had negative apl at birth and born to mothers with primary APS who were treated during pregnancy with low molecular weight heparin. No comparison was made as to what the baseline prevalence of these neurodevelopmental outcomes are in the general pediatric population. A single center retrospective study was aimed to investigate autism spectrum disorders in babies born to mothers with APS compared to mothers with SLE [43]. Although the group concluded that autism can be seen in babies born to mothers with APS, no comparisons to healthy controls were made further supporting the need for larger cohort studies. De Novo Neonatal APS A Bsecond hit^ mechanism of thrombosis (i.e., prematurity, stress of delivery, dehydration, indwelling central lines, sepsis, and congenital thrombophilia) has been proposed for neonates with de novo apl [3, 44 ]. A recent literature review of neonatal APS uncovered 33 cases of which 11 represented de novo cases based on neonatal presentation of thrombosis, positive apl and negative apl in the mother or cord blood and/or non-penetrable antibodies (IgM). Mostly all de novo cases were found to have an additional acquired thrombotic risk factor associated (infection, central vein catheter, dehydration, gestational diabetes, and congenital thrombophilias) [44 ]. Another study on infants with confirmed perinatal arterial ischemic stroke or cerebral sinus vein thrombosis underwent thrombophilia workup of which 49/62 had apl checked [3]. Twelve were found to have persistently elevated apl and prospectively followed. Ten of the 12 infants had their apl decrease to normal range within 2.5 years. None showed recurrent thrombosis or other apl related manifestations during the median 3.5 years of follow-up [range 9 months 19 years], with only one having received anticoagulant treatment. Although fulfilling criteria for APS, these patients may represent a subgroup in which the disease is transitory, does not recur, and may not require anticoagulant therapy, unless other risk factors are prevalent. Longitudinal and larger cohort studies are needed to further investigate. Pediatric APS Pediatric APS is determined by occurrence of thrombosis in the setting of a persistently positive apl. The criteria were developed in order to facilitate research purposes for adult APS and may fail to classify a subgroup of Bnon-classical^ pediatric patients that fall along the apl spectrum without thrombotic manifestations [24 ]. An international registry of pediatric patients with APS (Ped-APS Registry) was initiated in 2004 to foster and conduct multi-center, controlled studies with a large number of pediatric APS patients. Patients under the age of 18 years that fulfilled APS criteria adapted to pediatrics (see Table 1) were included and patients were excluded if they were infants born to mothers with APS or infants with congenital thrombophilia [24 ]. Currently, 144 patients are enrolled and analysis of the registry data of 121 patients in the registry have been published revealing thrombotic events of which 72 (60 %) were venous, 39 (32 %) arterial, 7 (6 %) small-vessel, and 3 (2 %) mixed arterial and venous [24 ]. Non-aPL Risk Factors Risk of thrombosis in apl-positive patients rises with increasing number of thrombotic risk factors [45 47] with approximately half of adult APS patients with thrombosis having at least one non-apl thrombotic risk factor at the time of their vascular event [48, 49]. The most common diseases associated with venous thromboembolism (VTE) in children include congenital heart disease, malignancies, and APS [50]. Both inherited and acquired risk factors play a role in the development of thrombosis in children, with acquired risk factors being more common. The presence of a central venous catheter is the most common risk factor for thrombosis in all pediatric patients [27]. Although some pro-thrombotic risk factors may overlap with adults (e.g., smoking and oral contraceptive use in adolescents), children generally have less acquired pro-thrombotic risk factors (e.g., hypercholesterolemia, atherosclerosis, and pregnancy) [51]. Instead, inherited pro-thrombotic risk factors (e.g., factor V Leiden mutation, protein C or S deficiency, prothrombin gene mutation, etc.) appear to be more common in children with APS and were found in 45 % (13/29) of the children tested from the pediatric APS registry [24 ], keeping in mind that the general prevalence of inherited thrombophilia disorders in children with VTE is low and similar to that of the general population [52 54]. For much of childhood, the vascular health and decreased thrombogenic potential of Virchow s triad favors a low risk environment. In general, thrombosis is a very rare event in the pediatric population and the percentage of aplrelated thrombosis in children [with inherited prothrombotic risk factors] appears to be higher than in adults [55, 56, 57]. Future research needs to develop a plan specific to children. Considering the lack of as many additional comorbid conditions as seen in adults, it makes it challenging to extrapolate prophylactic treatment or management regimens from adult data to children. Additionally, studies of risk need to be stratified by age and include surveillance of the less than 1 year old

5 Curr Rheumatol Rep (2015) 17: 27 Page 5 of group which has a higher event rate due to developmental hemostatic changes [21] and extend this to explain why children from greater than 1 year of age to pre-pubertal have lower rates of thrombotic events. Neurological Manifestations The most common neurologic manifestation in adult and pediatric patients is stroke or transient ischemic attack due to thrombosis or cerebral ischemia. Non-thrombotic neurologic dysfunction may also occur due to immune-mediated vascular, neuro-inflammatory, and direct neuronal effects [58]. Neurological deficits from small vessel thrombosis not picked up on magnetic resonance imaging may manifest with electroencephalography abnormalities [59]. Pediatric patients may have a higher incidence of migraine, epilepsy, and chorea, but these are mostly based on case reports [60, 61]. In the Ped-APS Registry, of the 19(16 %) children presenting with associated non-thrombotic clinical manifestations at the time of their initial thrombotic events, 7 % had migraine, 4 % chorea, 3 % epilepsy, 1 % mood disorder, and 1 % psuedotumor cerebri [24 ]. One cohort of children with lupus found the prevalence of aβ 2 GPI antibodies to be statistically higher in pediatric lupus patients with neuropsychiatric disease than in those without [62]. Specifically, a persistently positive LA showed a significant association with chorea [62]. However, apl were not associated with non-thrombotic neurologic manifestations in other pediatric lupus cohorts [63, 64]. A relation between epilepsy and apl in 142 young patients tested for acl and aβ 2 GPI has shown approximately 30 % of patients with epilepsy were positive for at least one subtype of apl (acl >10 units and aβ 2 GPI cut off points calculated as the mean value plus two standard deviations) with positivity confirmed on repeat testing 6 weeks later [65]. Whereas another cohort of 60 patients with epilepsy found only 1 child had acl antibody, 6/43 patients were LA positive and aβ 2 GPI positivity was not found in any [66]. Persistently positive apl were seen in 16.3 % of children with migraine and 16.7 % with tension-type headache with the prevalence of apl not differing significantly between patient groups and healthy controls [67]. Cognitive dysfunction may manifest as memory loss or inattention [25, 68] and may be easily missed in a child who is still developing their cognitive capabilities or may be dismissed due to a non-organic learning disability. In the pediatric population, testing for apl and/or obtaining an apl history may be reasonable in those already identified to have a learning disability, and researchers should seek to obtain larger cohort studies to investigate if there is a connection to apl. The Childhood Autism Risks from Genetics and Environment study enrolled 109 children into 3 groups: those with autism spectrum disorder (ASD), developmental delay (DD), and typically developing (TD) controls. They found that the ASD group have increased aβ 2 GPI antibodies compared to the DD and TD control groups and increased acl antibodies compared to the TD controls [69]. Major limitations to be noted were mean ASD IgG acl levels were less than 5 GPL U/ml and no apl or family apl history was taken. However, this study shows that large subject ascertainment to investigate neurological manifestations in relation to apl in a cohort of children is feasible and can be replicated in future studies addressing these limitations. Hematological Manifestations The most common non-thrombotic clinical manifestations are hematological disorders [70]. Hematological manifestations may be more prominent in pediatric APS with thrombocytopenia, hemolytic anemia, leucopenia, and rarely LA hypoprothrombinemia syndrome due to high affinity antiprothrombin (Factor II) antibodies [71]. How Is APS Different in Children Compared to Adults? Female to Male Ratio The mean age at disease onset in pediatric APS is 10.7 years (range 1.0 to 17.9 years) [24 ], with only a slight female predominance with a female-to-male ratio ranging from 1.2:1 to 1.5:1 [72, 73]; whereas in adult APS studies, the female-to-male ratio is reported to be over 5:1 [72, 74]. Primary APS and Secondary APS In the pediatric age group, % of cases are primary APS without other underlying disease [24 ]. Children with primary APS are younger and have a higher frequency of arterial thrombotic events than are children with secondary APS who are older with a higher frequency of venous thrombotic events [24 ]. Some children who initially present as primary APS may later develop overt SLE [72, 75]. The chance of progression of primary APS into secondary APS may be higher in children than compared to adults. SLE and lupus-like disease account for the majority (83 %) of pediatric secondary APS [24 ]. During a 6-year follow-up period, 4/14 (21 %) children who were initially diagnosed with primary APS progressed to have either SLE or lupus-like disease, compared to a study in which 17/128 (13 %) adults with primary APS developed SLE or lupus-like disease during a median followup of 8 years [75, 76]. A review of studies that investigated the clinical significance of apl in pediatric SLE showed a prevalence of 44 % for acl, 40 % for aβ 2 GPI, and 22 % for LA, although data about autoantibody titers and antibody persistence were not

6 27 Page 6 of 13 Curr Rheumatol Rep (2015) 17: 27 available in all studies that were included in the review [77]. The cases of APS have also been reported in association with other pediatric autoimmune diseases, including juvenile idiopathic arthritis (JIA) [78, 79], Henoch Schönlein purpura [80, 81], Behçet disease [24], hemolytic-uremic syndrome [82], juvenile dermatomyositis [83], and rheumatic fever [84, 85]. In JIA, acl has been reported in 7 to 53 % of patients, but aβ 2 GPI and LA (felt to be more specific for thrombosis risk) were detected in fewer than 5 % of patients [86, 87]. In contrast to patients with SLE, these patients very rarely develop apl-related thrombotic events [88]. Non-aPL Risk Factors Generally, children lack the common pro-thrombotic risk factors of adulthood such as atherosclerosis, hypertension, cigarette smoking, and oral contraceptive use. Therefore, the proportion of thrombosis that is attributable to apl may be higher than in the adult population [77]. apl Profile Only 33 % of pediatric APS patients were found to have triple positivity for all three apl subtypes with the remaining 67 % testing negative for one or two of the apl tests [24 ]. This emphasizes the importance of routine testing for all 3 apl subtypes. Pediatric patients have a higher frequency of LA (72 %) than adults (40 54 %) [24, 73, 74]. A high percentage of children with persistently positive apl apparently do not present with overt thrombotic events. A retrospective study of 100 children with positive apl evaluated at the tertiary care pediatric hospital demonstrated that thromboses occurred only in 10 % of patients, while the non-thrombotic apl-related clinical manifestations alone were observed in 77 % of patients [89]. apl in Healthy Children Low levels of apl can be found in up to 25 % of apparently healthy children, which is higher than the rate seen in the normal adult population [22, 90, 91]. These apl are usually transient and could be the result of previous infections or vaccinations [92 95]. In apparently healthy children, the estimated frequency of acl ranges from 3 to 28 % and of aβ 2 GPI, from 3 to 7 % [90, 91]. Immunoglobulin levels (and subclasses) vary by age and may require age-specific normal values [96]. Lupus anticoagulant have also been described in apparently healthy children, usually as an incidental finding of prolonged aptt during pre-operative coagulation screening [22, 97]. The risk of future thrombosis is very low in otherwise healthy children who were incidentally found to have positive apl [22]. In a number of studies, and in clinical practice, prolonged prothrombin time (PT) or aptt is used as a screen for LA (although many other factors can produce this effect). Alternatively, false negative LA assays that use aptt as a screen are caused by elevations in factor VIII, such as in SLE and inflammatory disease. Also, because of changes in coagulation factor levels, normal values for LA should be established by age group. Clinical Manifestations The clinical expression of apl in children is modified by several characteristics of the pre-pubertal pediatric age group, such as the immaturity of the immune and other organ systems, relative health of the vasculature in pre-pubertal children (one aspect of Virchow s triad), the absence of common prothrombotic risk factors often present in adults, the lack of pregnancy morbidity, and the presence of routine immunizations and frequent exposure to viral and bacterial infections [98 100]. Developmental hemostasis again plays a role as post-pubertal children approach adult levels of coagulation proteins. Post-pubertal children are exposed to birth control pills, illicit drugs, smoking, alcohol as well as being in the peak age for childhood SLE and other autoimmune diseases. Data from the Ped-APS Registry have provided information on the spectrum of thrombotic and non-thrombotic clinical manifestations in children. At the time of the initial thrombotic event in children with definite APS, the estimated frequencies of associated non-thrombotic manifestations were 38 % for hematological manifestations, 18 % for dermatological manifestations, and 16 % for non-thrombotic neurological manifestations [24 ]. Cerebrovascular events (sinus venous thrombosis and ischemic stroke) are much more frequent (32 %) in pediatric APS compared to adults (16 21 %) [24 ]. Non-thrombotic Manifestations The consensus criteria for the diagnosis of APS were developed for classification of adult patients with APS and may fail to recognize a subgroup of patients with apl-related nonthrombotic clinical manifestations that should also be considered in the pediatric population [72]. Compared with the adult population, pediatric patients with APS have a higher frequency of Evans syndrome, Raynaud phenomenon, migraine headache, and chorea [24 ]. Pregnancy morbidity, which is one of the two clinical criteria for definite APS in adults, is not applicable to the pediatric population, and it is possible that current consensus criteria may fail to recognize a subgroup of pediatric patients who do not present with vascular thrombosis but demonstrate typical non-thrombotic clinical features and fulfill the laboratory criteria for APS [24 ]. Lupus anticoagulant hypoprothombinemia syndrome is a rare condition characterized by a severe bleeding diathesis associated with the presence of LA. It has been described in both primary APS

7 Curr Rheumatol Rep (2015) 17: 27 Page 7 of and APS associated with SLE and is often preceded by a viral infection [ ]. This complication has been attributed to the presence of anti-prothrombin antibodies that cause rapid depletion of plasma prothrombin. Higher Recurrence Rate Some studies suggest that the risk of recurrent thrombosis may be higher in children with APS although this may be age dependent. In one study, 19 % of pediatric APS patients developed a recurrent thrombotic event; whereas, there are reports of only up to 11 % of adults with APS who develop recurrent thrombosis [24, 104]. Data from the Ped-APS Registry showed that of the 23 patients with recurrent thrombosis, 14 were initially venous, 8 arterial, and 1 had renal thrombotic microangiopathy. Of the patients with initial venous thrombosis, 86 % had recurrent venous events and of the patients with initial arterial thrombosis and 75 % had recurrent arterial events suggesting recurrence usually occurs in the same type of blood vessel [24 ]. Malignancies Pediatric APS is less frequently associated with malignancy, compared to adults with APS and this again may be due to the relative health of the vasculature in pre-pubertal children. Data suggest that APS associated with malignancies accounts for less than 1 % of all children with APS [24 ]. There have been only isolated case reports of the association of apl with thrombotic events in children with various malignancies, including solid tumors and lymphoproliferative and hematological malignancies [105, 106]. Antiphospholipid-related thrombotic events associated with malignancies are more common in elderly patients, particularly in association with solid tumors [107]. Pediatric CAPS Catastrophic APS is a rare, potentially life-threatening subset of APS, characterized by acute, multiple small-vessel occlusions that can lead to multi-organ failure and a high mortality rate [108, 109]. This syndrome is defined as clinical involvement of at least three organ systems and/or tissues over a very short period of time with histopathological evidence of small vessel occlusion and laboratory confirmation of the presence of apl [108, 109]. Although large vessel occlusions do occur in CAPS, the clinical picture is usually dominated by aggressive microvascular disease affecting kidney, liver, central nervous system, heart, lung, and skin [24 ]. Preliminary classification criteria for CAPS were established in 2002 at the 10th International Congress on apl [108] and validated in 2005 [109]. These criteria define Bdefinite^ and Bprobable^ CAPS; however, an overlapping CAPS spectrum exists including apl-positive patients who do not fulfill criteria, but need to be closely watched for the development of CAPS. In the spectrum are those with multiple organ thromboses and/or thrombotic microangiopathies characterized by predominant hematologic manifestations. On the far end of this spectrum is thrombotic storm, which is characterized by rapid onset multiple large vessel thromboses, but may or may not have positive apl confirmation and has been seen in case series of children [110]. Updated diagnostic algorithms for CAPS can be found elsewhere [111, 112 ]. CAPS Registry Aside from various case reports and series, what we know about the clinical characteristics of pediatric CAPS comes from the international CAPS Registry of the European Forum on Antiphospholipid Antibodies that published a descriptive analysis of its 45 pediatric cases [113 ]. The cases were identified through the literature and personal communications with the most updated information found at en/web/caps. The clinical, laboratory features, treatments and outcomes were not significantly different in children compared to adults. A higher prevalence of infection as a precipitating factor in pediatric CAPS (60.9 % versus 26. 8%, p<0.0001) compared to adult patients in the registry was identified. However, the apl profile of the included registry patients was not reported in order to adequately determine if the apl was Bclinically significant^ or may have been just acting as a bystander to an infectious process. A majority of the patients (68.9 %) had primary APS and 28. 9%hadSLE.Peripheralvesselthrombosis(52.2%versus34. 3%,p=0.017) was more prevalent in pediatric patients compared to adults. In addition, CAPS was the first manifestation of APS more frequently in pediatric patients (86.6 versus 45.2 %, p<0.001). Pediatric patients showed a trend of lower mortality, although the difference was not statistically significant (26.1 versus 40.2 %; odds ratio, 1.9; 95 % confidence interval, ; p=0.063), perhaps due to relative vascular health. Treatment Primary Thrombosis Prophylaxis Asymptomatic Positive apl Pediatric data are lacking and treatment recommendations stem from adult practice. Although an earlier expert panel came to a consensus on low dose Aspirin ( mg daily) for prevention of thrombosis of asymptomatic adult patients with positive apl [114], a recent task force provided

8 27 Page 8 of 13 Curr Rheumatol Rep (2015) 17: 27 evidence-based recommendations on the treatment of asymptomatic positive apl carriers. This approach takes into account the apl profile, cardiovascular risk factors and clinical situation to determine high-risk status for treatment initiation. [115]. Although limited by a small sample size, the only placebo-controlled randomized controlled trial [116] failed to show a benefit of aspirin (with a 2 year follow-up). Risk changes with age (developmental hemostasis) and healthy children incidentally found to have apl have very rare risk of thrombotic events. Prophylactic treatment is controversial considering the risk of bleeding during play and sports outweighing the unproven benefit of low-dose aspirin. Clinical judgment is often necessary and should take into account congenital or acquired pro-thrombotic risk factors and the apl profile. Strict control of other cardiovascular risk factors is needed in every child with apl as a primary thromboprophylaxis. Thromboprophylaxis with lowmolecular-weight heparin may be considered in high-risk situations (surgery, long-lasting immobilization, etc.) [115]. Underlying Autoimmune Disease and Positive apl Underlying autoimmune disease, such as SLE, is a prothrombotic condition that increases risk of thrombosis if positive apl is present [117]. Retrospective studies suggest both pediatric and adults with SLE and apl have a 50 % chance of suffering a thrombotic event within 10 year. In these cases, primary prophylaxis with aspirin (3 5 mg/kg/day) is sometimes practiced, although the strength of this recommendation is controversial [115]. Recently, a meta-analysis of patientlevel raw data obtained directly from the authors of 5 international cohort studies (2 prospective and 3 retrospective) looked at the effect of low-dose aspirin treated versus not treated apl carriers on risk of first thrombosis and found a 0.43 HR (95 % CI ) [118]. Almost half of the patients included had SLE, however it also included 30 % asymptomatic apl carriers without underlying autoimmune disease. Separate subgroup analysis of SLE and asymptomatic apl carriers showed a protective effect of aspirin (HR 0.43, CI ) against arterial events, although the study was not powered for this analysis. The study may also be subject to bias from the 5/11 authors who chose to participate. Hydroxychloroquine appears protective against development of both venous and arterial thrombosis in adult SLE patients and may be considered an option [119], although the strength of this recommendation is also controversial [115]. Secondary Thrombosis Prophylaxis Recommendations for secondary thrombosis prophylaxis have been based on experience and adapted from published adult data [120]. This is an additional area where prospective pediatric studies are needed. Treatment of Catastrophic APS in Children Treatment considerations [108, 121, 122] have been published in adults. There are no guidelines specific to pediatric CAPS with only case reports reporting on use of various treatments. The pediatric CAPS registry of 45 patients reported treatment with anticoagulants (77.8 %), corticosteroids (75.6 %), plasma exchange (40 %), intravenous immunoglobulins (37.8 %), and cyclophosphamide (24.4 %) with various combination treatments, the most common being anticoagulant plus steroids at 20.9 % [113 ]. Rituximab has also been used successfully in the case reports [123, 124] and has been described in 20 patients from the pediatric CAPS registry [125 ]. Treatment of APS-Related Events (New Agents) Traditionally, thrombotic events are treated acutely with heparin, followed by long-term anticoagulation with vitamin K antagonists, such as warfarin. Although not specifically tested in the pediatric population, various new treatments for APS are being studied including oral direct thrombin or anti-factor Xa inhibitors, non-warfarin/heparin anticoagulants, hydroxychloroquine, statins, B-cell inhibitors, complement inhibitors, and peptide therapies [126 ]. Future Studies Studies need to be stratified by age into different groups, especially considering those less than 1 year and those postpubertal, given the change in hemostatic risk. Antiphospholipid antibody assays need to have age-matched controls. Instead of studying small groups of APS patients, large cohorts of healthy children or children with clinical problems (such as autism or learning disability) should be studied for APS symptoms, family history, and apl testing. We would encourage the use of the proposed manuscript submission recommendations from the Sydney Consensus conference [1]. Studies should employ strict research classification criteria (Table 1) in order to validate these existing criteria, as well as inclusion of other clinical parameters and assays in order to introduce new information to the literature for future analysis and validation. Data should be analyzed by clinical diagnoses as well as research criteria (i.e., numbers of patients and what types/situations are included/excluded by applying the research classification criteria). Lupus anticoagulant should be detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/phospholipid-dependent antibodies) [127]. Ideally, centralized core laboratories should be utilized in order to avoid assay and kit variations and to report as close to true determinations of apl as possible.

9 Curr Rheumatol Rep (2015) 17: 27 Page 9 of Children with APS may be under-recognized and undertreated with a higher rate of recurrence. Therefore, risk stratification for secondary thrombosis needs to be further investigated. Longitudinal studies to assess the different intensity of anticoagulation regimens and the effect of these on the risk of recurrent thrombosis during follow-up are encouraged. Authors are encouraged to continue publishing case reports and case series as these also add information to the literature and should enter these cases in to national databases and web-based registries as well. Authors of these reports as well as studies with small sample sizes are cautioned about drawing conclusions and making recommendations based on non-statistically significant numbers. Recommendations that are not statistically supported may have undesirable clinical consequences. Information on incidence and prevalence of apl and APS and risk of thromboses in the general pediatric population as well as in other disease entities (such as autism, learning disabilities, cognitive dysfunction) will come from large pediatric databases. This may best be accomplished in connection with national registries that have been established for years/decades. Studies that are performed in high risk populations (such as those with rheumatic diseases) only produce data and recommendations for treatment of those high risk populations and unfortunately are limited by small sample size or heterogeneous cohorts. The data collected in rheumatologybased databases, while helpful for rheumatology patients, may be too focused and not generalizable. One possible avenue to obtain treatment data on large cohorts is to design studies akin to the Warfarin versus Aspirin Recurrent Stroke Study (WARSS) and Antiphospholipid Antibodies and Stroke Study (APASS). The APASS was a cohort study within WARSS [128, 129 ]. These are prospective studies where the investigators can specify in advance data sampling/collection (i.e., family history queries, history of APS related events, physical exam features, associated risk factors, assays, and sample collection/storage) and are generally powered for statistical analysis. Another avenue is to utilize less obvious patient populations with diseases (such as sickle-cell disease [130, 131]) that have Bassociated^ apl but also have other more well-known factors involved in the vaso-occlusive events. The International Congress on Antiphospholipid Antibodies takes place every 3 years to discuss the recent advances and future directions in APS. In preparation to the 15th International Congress on apl ( September 2016, Istanbul, Turkey), a Pediatric APS International Task Force has been created for the first time. The Task Force members including the authors of this review paper will continue to collect and analyze studies published by the summer of 2016 for a subsequent review article. Additional expertise and personnel will be added to the Task Force as the data require. Data based on all published studies and registries on APS criteria and treatment applicable to children and neonates will then be presented and discussed at the Istanbul meeting followed by a post-conference summary paper. Conclusions In summary, the published BClassification Criteria^ are guidelines for research studies. Published data on pediatric APS are sparse and is based on limited populations with rheumatic disease or Bclinical events^ (and thus does not represent the general pediatric population). New large studies are needed on general pediatric populations (age stratified) to establish risk. Only after risk is defined that recommendations on treatment can be proposed. Risk is a moving target in growing children due to developmental hemostasis. Data are desperately needed on the use of the new antiplatelet drugs, dual antiplatelet therapy, new oral anticoagulants/inhibitors, and parenteral anticoagulants in the Bat risk^ pediatric APS population. The charge of the Pediatric APS International Task Force is to review the current literature on pediatric APS (including the impact of apl in pediatric thrombosis) in an evidence-based manner and report at the 15th International Congress on apl, which will be held in Istanbul, Turkey in September Acknowledgments The authors would like to acknowledge the suggestions and recommendations of Patricia Massicotte, M.D. of the University of Alberta. Compliance with Ethics Guidelines ConflictofInterest Cassyanne L. Aguiar, Arzu Soybilgic, Tadej Avcin, and Barry L. Myones declare that they have no conflict of interest. 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