Antiphospholipid antibodies and cerebrovascular thrombosis in the pediatric population: Few answers to many questions

2. Antiphospholipid antibodies and cerebral thrombosis 2.1. Lupus anticoagulant In neonates and children, LAC are sometimes found incidentally due to prolongation of activated partial thromboplastin time (20). As LAC can be transient and associated with infections and transplacental passage (21, 22), they are not usually associated with clinically relevant complications (23). Therefore, the differentiation between de novo and acquired LAC has important therapeutic implications and is crucial for prognosis (24). 2.1.1. Perinatal ischemic stroke Before LAC had been isolated in neonates, the transplacental transport of LAC had been described in case reports to be associated with perinatal ischemic strokes (25). The reports on the existence of de novo LAC in neonates with perinatal stroke and no other prothrombotic risk factors denoted the role of LAC (table 2). Although limited, the data on the implication of LAC in perinatal stroke is contradictory. The confirmation test is important to specify whether LAC had a true contributory role to perinatal stroke. In the only case where LAC was confirmed positive, monoparesis persisted upon followup. Therefore, the persistence of LAC can be associated with worse outcomes after perinatal strokes, but this observation needs further studies to be tested. Reference Type Scenario Result Confirmed Management/Outcome de Klerk et al. (26) Case report 3-day-old Male Left MCA stroke LAC 18.9 GPL units/mL Negative after 1 month Y Phenobarbital 12 months: No neurological complications Sousa et al. (10) Case report 8-hour-old Female Right caudate and lenticular nucleus, with extension to the cerebral peduncle Positive LAC Y Aspirin 12 months: Monoparesis grade 3 of the left upper limb. Berkun et al. (24) Prospective cohort 5 patients with perinatal stroke 5/5 (100%) 1/5 (20%) after 3 years Y 4 with no anticoagulation 1 with indefinite anticoagulant Table 2. Literature data describing the prevalence of de novo lupus anticoagulant in perinatal ischemic stroke. LAC: Lupus anticoagulant; MCA: Middle cerebral artery; GPL: 1 microgram of IgG antibody; Y: Yes; N: No 2.1.2. Neonatal sinovenous thrombosis Few characteristics are known about neonatal sinovenous thrombosis, because it is a rare disease. One of these characteristics is its association with thrombophilia. Mutation in factor II G20210A is found in 11% of neonates with sinovenous thrombosis, while factor V G1691A mutation is present in 4.9% of patients (27). Although LAC has the ability to affect the blood flow in small cerebral blood vessels 6 leading to ischemic damage to brain tissue (28), there has been no evidence so far on its involvement in the pathogenesis of neonatal sinovenous thrombosis. 2.1.3. Pediatric ischemic stroke Pediatric ischemic strokes have been linked to connective tissue diseases, such SLE (29). Compared to perinatal stroke, there are more studies that discussed the role of LAC in pediatric ischemic stroke (table 3). Despite that 4 of these studies reported a prevalence of more than 10%, the study which enrolled the greatest number of patients reported a prevalence of 3.5% (30). It is evident that the confirmatory test leads to a lower prevalence. Therefore, in the absence of other pro-coagulative factors, either durable positive LAC or other aPL could be contributing to arterial ischemic strokes in children. Reference Type Population Result Confirmed Management/Outcome Kenet et al. (15) Casecontrol 58 children with stroke 6/58 (10.3%) Y NR Bonduel et al. (30) Prospective cohort 112 consecutive children with acute ischemic stroke 4/112 (3.5%) Y 1 patient on acenocoumarol with no recurrence Balasa et al. (31) Casecontrol 22 children with ischemic cerebrovascular disease 3/10 (30%) N NR Angelini et al. (32) Case series 13 children with cerebral ischemia 2/13 (15.4%) 1/13 (7.7%) on second determination Y NR Berkun et al. (33) Prospective cohort 11 children with pediatric APS and cerebral vascular ischemic lesion 6/11 (54.5%) Decreased titers with time Y 1 treated with prolonged LMWH and aspirin without complications Gattorno et al. (34) Prospective cohort 14 children with primary APS 5/14 (35.7%) Y NR Table 3. Literature data describing the prevalence of lupus anticoagulant in pediatric ischemic stroke. APS: Antiphospholipid syndrome; Y: Yes; N: No; LMWH: Low-molecular-weight heparin; NR: Not reported 2.1.4. Pediatric sinovenous thrombosis While LAC have been associated with DVT and Budd-Chiari syndrome in children (35), a weak evidence exists on its association with pediatric sinovenous thrombosis. In the two studies that assessed the prevalence of LAC among pediatric patients with sinovenous thrombosis, other prothrombotic conditions were also assessed (table 4). In general, the association of prothrombotic disorders with childhood sinovenous thrombosis remains controversial. Some of the literature studies support the involvement of protein C deficiency (36), while others highlight the role of thrombophilia genetic mutations (37). Among LAC positive children, one study did not record positivity for thrombophilia genetic mutations such as factor V Leiden or prothrombin G20210A mutation (30). On the other hand, the other study found one positive patient that had co-existent protein C deficiency (38). 7 Reference Type Population Result Confirmed Management/Outcome Bonduel et al. (30) Prospective cohort 38 consecutive children with cerebral venous thrombosis 2/38 (5.2%) Y