Anti-Phospholipid Syndrome: Clinical Spectrum and Therapeutical/Prophylactic Strategies in the Pediatric Population

European Review for Medical and Pharmacological Sciences 2008; 12: 47-53 Anti-phospholipid syndrome: clinical spectrum and therapeutical/prophylactic strategies in the pediatric population

D. RIGANTE, S. GASPARI, G. BERSANI, A. STABILE

Department of Pediatric Sciences, Catholic University of Sacred Heart – Rome (Italy)

Abstract. – Anti-phospholipid syndrome recognize various negatively-charged anionic (APS) is a potentially life-threatening autoim- phospholipids as cardiolipin, phosphatidylser- mune condition characterized by the presence ine, phoshatidylethanolamine and phos- of anti-phospholipid antibodies (aPL) giving rise to increased hypercoagulability, which induces phatidylinositol, but mainly phospholipid-bind- venous or arterial thrombotic events at whatever ing proteins and phospholipid-protein complex- age and recurrent fetal loss in the fertile age. es. Their most relevant effect is the interference Antigens that are targeted by aPL include cardi- with phospholipid-dependent coagulation as- olipin and beta2-glycoprotein I. Primary APS is says and the subsequent prolongation of clotting defined in the absence of an underlying disease, times. Various theories have tried to explain the while secondary APS is observed in the context of another established pathological condition. thrombophilic capacity of aPL. A first theory APS has a wide variety of clinical signs and hypothyzes that various coagulation proteins serological characteristics. This paper describes bind membrane phospholipids of endothelial the current approaches towards diagnosis, ther- cells presenting a defective apoptosis with sub- apeutic modalities and secondary prevention sequent creation of aPL, targeted towards the applied to children. new epitope phospholipid-protein complex, ac- tivating directly the vascular endothelium. Other Key Words: proposed mechanisms for the hypercoagulable Anti-phospholipid syndrome, Children. effect of aPL include activation of platelets to enhance endothelial adherence and predisposi- tion to thrombosis, production of antibodies against coagulation factors, including prothrombin, protein C and S, naturally provided with Introduction the faculty of inhibiting clotting factors, and re- action of aPL to oxidized low-density lipopro- teins, with subsequent damage to the endothe- Anti-phospholipid syndrome (APS) is a dis- lial cells which predisposes these individuals to order described for the first time in 1980 char- atherosclerosis and myocardial infarction2. acterized by the presence of anti-phospholipid antibodies (aPL) in the serum and by a clinical picture which can display intravascular thrombosis (in subjects of whatever age) or patholog- General Features of the ic exits of pregnancy (in fertile women). APS Anti-phospholipid Syndrome represents the most frequent cause of acquired thrombophilia also in the pediatric age1. An al- The simultaneous presence of aPL in the teration of the homeostatic regulation of blood serum and thrombotic events defines the APS: coagulation occurs. However, the mechanisms aPL serologic positivity consents to assess a risk of thrombosis are not yet defined. A pivotal role of 0.5-30% for new thrombotic episodes3. in the pathogenesis of APS is carried out by Thrombosis can involve whatever vascular dis- aPL, which are specific markers for APS: they trict, both venous and arterial: in the child deep include a heterogeneous group of antibodies and veins of limbs are the most involved vessels with

Corresponding Author: Donato Rigante, MD; e-mail: [email protected] 47 D. Rigante, S. Gaspari, G. Bersani, A. Stabile the subsequent risk of pulmonary embolism, fol- sus11. Sometimes APS arises in subjects with lowed by cerebral and coronary arteries4. During neoplasms, infectious diseases, after vaccinations the fertile age APS is basically characterized by (with recombinant hepatitis B vaccine and in- pregnancy complications which follow intra-fetal fluenza virus vaccine) or in consequence of spe- or intra-placental thrombotic events and infarc- cific drugs, which might ultimately provide a tions, which give rise to recurrent first-trimester clue to the etiology of APS, as shown in the miscarriage, second- or third-trimester fetal death Table I12. Recent literature suggests that the oc- and premature childbirth5. Three classes of aPL currence rate of APS in adult patients with sys- are historically associated with APS: lupus-like temic lupus erythematosus is 34-42%, but no epi- anticoagulant (LAC), anti-cardiolipin antibodies demiologic data are available for pediatric pa- β (ACL) and anti- 2-glicoprotein I antibodies tients. The prevalence of serologic aPL positivity β 6 (A 2GpI) . In particular, the antigen specificity is 30% in children with juvenile idiopathic arthri- of LAC is still poorly characterized and oxidized tis, independently from the evidence of throm- phospholipids or plasma coagulation proteins are botic complications13. It is mandatory to under- believed to be its main target. LAC, interfering line the possibility of a “catastrophic” variant of with clotting factors X and V, as well as platelets APS, also known as Asherson’s syndrome, and prothrombin, can be detected indirectly mea- caused by the large production of microthrombi suring the activated partial thromboplastin time in various vascular districts and characterized by (or aPTT), kaolin clotting time and diluted Rus- accelerated systemic involvement leading to mul- sell’s viper venom test which appear prolonged. ti-organic failure with massive thromboembolism ACL were discovered in 1983, react primarily to and infarctions in central nervous system, kid- membrane phospholipids, such as cardiolipin and neys, lungs and liver. Among the precipitating phosphatidylserine, are quantified with radio-im- factors of a “catastrophic” APS we have to list munologic assay and mostly IgG isotype corre- infections, surgical procedures, anticoagulant β lates with the thrombotic events. A 2GpI, direct- treatment interruption, oral contraceptives and β 14,15 ed towards 2-glicoprotein 1, also known as neoplasms . apolipoprotein H, a natural anticoagulant sub- stance capable of binding negative-charged phospholipids, were discovered in 1990 and are believed to be the main effectors of APS7,8.Al- Anti-phospholipid Syndrome though aPL are clinically linked to APS, whether in the Pediatric Age they are the triggers of this pathology or a mere epiphenomenon of the disease is unclear. It is The major part of clinical manifestations de- known that aPL occur in up to 5% of healthy in- scribed in adults with APS have been reported in dividuals, both children and adults. aPL preva- children too. From the revision of 50 pediatric lence is higher in healthy children (5-20%) in patients with history of APS it has been observed comparison with the one observed in healthy that the female sex is more frequently involved, adults (1-5%), though the clinical relevance of that the onset age is extremely variable (from the this difference is still debated9. first infancy until the late adolescence) and that only a small percentage of patients displays a positive familiarity for clinical events which seem aPL-related12. The presentation clinical pic- Variants of tures of APS include venous or arterial vascular Anti-phospholipid Syndrome thrombosis, listed in the Table II16. Superficial or deep veins of the inferior limbs are the sites APS can occur in patients without any evi- preferably affected by thrombotic events in 29- dence of an associated disease (primary APS) or 55% cases. Sometimes pulmonary embolism can in association with systemic lupus erythematosus be observed, but it seldom gives rise to pul- and other established rheumatologic/autoimmune monary hypertension. Other sites of venous disorders or diseases which are not mediated by thrombosis include inferior and superior vena ca- the immune system, (secondary APS)10. The va, renal, mesenteric, hepatic and retinic veins. most recent study coordinated by Cervera et al. in Cerebral arteries are the sites where arterial over 1000 patients has revealed that 37% of APS thrombosis are most frequently diagnosed, result- is associated with systemic lupus erythemato- ing in transient ischemic attacks (TIA) or true

48 Anti-phospholipid syndrome

Table I. Diseases associated with anti-phospholipid antibody positivity.

Systemic autoimmune diseases Systemic lupus erythematosus Rheumatoid arthritis and juvenile idiopathic arthritis Systemic scleroderma Sjögren syndrome Dermatomyositis Vasculitic syndromes Polyarteritis nodosa Cutaneous leukocytoclastic vasculitis Behçet’s disease Infections Viral Acquired immunodeficiency syndrome (AIDS) Infectious mononucleosis Parvovirus B19-caused diseases Hepatitis C Epidemic mumps Chickenpox Bacterial Syphilis Septicemia Borreliosis (Lyme disease) Tuberculosis Infective endocarditis Protozoal Malaria Toxoplasmosis Malignant diseases Solid tumors Lung Thymus Ovary Primary malignant blood diseases Myeloid and lymphatic leukemia Polycythemia vera Myelofibrosis with myeloid metaplasia Malignant lymphoproliferative diseases Lymphoma and lymphosarcoma Mycosis fungoides and Sézary syndrome Paraproteinemias Monoclonal gammopathy Multiple myeloma Non-malignant blood disorders Idiopathic thrombocytopenic purpura Pernicious anemia Drugs Chlorpromazine Phenytoin Pirimetamine Chinidine Hydralazine Procainamide Propranolol Interferons Quinine Amoxicillin Other conditions Diabetes mellitus Autoimmune thyroiditis (Hashimoto’s disease) Inflammatory bowel disease (IBD) cerebral strokes17. The prevalence of aPL positiv- bral artery, is high, oscillating from 16 to 76%18. ity in children having presented events of is- Leg ulcers, sub-ungueal infarcts, painful necro- chemic nature in the central nervous system, tizing purpura, splinter hemorrhages and livedo mostly in the area supplied by the middle cere- reticularis have been described as possibile cuta-

49 D. Rigante, S. Gaspari, G. Bersani, A. Stabile

Table II. Sites involved by thrombotic events and clinical a frank hemolysis and of its consequences is un- manifestations in the anti-phospholipid syndrome of the pe- common. The association of thrombocytopenia diatric age. and hemolytic anemia (which is known as Involved Clinical “Evans syndrome”) is reported in few pediatric vessels manifestations cases of APS. Among renal diseases associated with APS in the child we enumerate thrombotic Veins microangiopathy and renal vein thrombosis. Limbs Leg swelling, localized edema Among gastrointestinal manifestations described and pain in children with APS, all secondary to thrombot- Lung Pulmonary thromboembolism (acute dyspnea) ic events, we point out Budd-Chiari syndrome Skin Livedo reticularis (caused by the obstruction of hepatic veins or in- Brain Cephalalgia, papilledema, ferior vena cava, with subsequent portal hyper- seizures, hemiplegia tension and ascites), intestinal ischemia, mesen- Kidney Peripheral edema teric and portal vein thrombosis. Aseptic necrosis Liver Budd-Chiari syndrome Eye Amaurosis, abnormal of femoral head is relatively frequent in the or- funduscopic examination thopedic workplace and its pathogenesis is de- Adrenal glands Addison’s disease (adrenal pending on the poor blood circulation to the ossi- insufficiency) fication center, due to the hypercoagulable state20. Neonatal APS is a clinical entity characterized Arteries BrainTransient ischemic attack (TIA) by neonatal thrombotic disease caused by or ictus transplacentally acquired aPL: the rare occur- Kidney rence of neonatal thrombotic events has been at- a) large vessels Renal infarction (pain and tributed to the lack of the most known “second hematuria) hit” risk factors in infants and to the low b) small vessels Thrombotic microangiopathy (hypertension) transplacental passage of subclasses of aPL with Limbs Digital ulcers, ischemia and high pathogenicity. Special concern is needed gangrena particularly when dealing with aPL-positive in- Heart Myocardial infarction, valvular fants who are exposed to other acquired throm- insufficiency botic risk factors (as central vascular catheters, Liver Hepatic infarction Gut Intestinal occlusion sepsis, prematurity and congenital heart diseases) and possibly inherited prothrombotic disorders (as antithrombin III, protein C or protein S defi- ciencies and factor V-Leiden mutation)21. neous manifestations of APS in the child. Cuta- neous ulcers begin more frequently in the pre-tib- ial face of legs, can be multiple or focal, intense- ly painful and leave atrophic scars. Livedo reticu- Diagnosis of laris (or livedo racemosa) is a skin manifestation Anti-phospholipid Syndrome typical of APS: it follows stagnant blood in the superficial venous capillaries dilated of skin of Criteria useful for the diagnosis of APS, per- thighs, legs or forearms. The association of live- taining to the clinical setting and laboratory tests, do reticularis and cerebro-vascular disease (char- were firstly ratified at Sapporo in 1999 and then acterized by signs of cerebral ischemia or pseu- modified at Sydney in 2005. APS can be diag- do-bulbar syndrome) identifies the Sneddon syn- nosed only in the presence of at least one clinical drome, though it is outstanding in the child. In criterium and one laboratory criterium. Tables III one third of pediatric patients the possibility of and IV describe into details the clinical and labo- thrombocytopenia and hemolytic anemia is re- ratory criteria which need to be demonstrated to ported; usually the decrease of platelet count is support the diagnosis of APS. In the presence of not complicated by hemorrhagic phenomena. a thrombotic event, venous or arterious, coagula- The pathogenesis of thrombocytopenia is not tion assays including aPTT, kaolin clotting time clear, though it might originate from the binding and diluted Russel’s viper venom time should be of aPL to membrane phospholipids of platelets19. texted in combination with serum ACL and β About 10-20% of children with APS can present A 2GpI evaluations. In addition aPL positivity a positive Coombs test, though the inspection of must be at “high titre” and verified at least twice

50 Anti-phospholipid syndrome

Table III. Clinical criteria for the diagnosis of anti-phospho- Table V. “Permanent” risk factors for venous thromboem- lipid syndrome. bolism.

Vascular thrombosis • Chronic venous insufficiency One or more clinical episodes of venous or arterial • Idiopathic familiar venous thromboembolic disease thrombosis occurring in any tissue or organ confirmed • Hyperhomocysteinemia (general prevalence: 2-16%) by ultrasound, echo-Doppler or histopathology exami- •Factor V G1691A (factor V-Leiden) (general preva- nations lence: 5-10%) •Protein C deficiency (general prevalence: 3%) Complications of pregnancy •Protein S deficiency (general prevalence: 3%) • One or more unexplained deaths of morphologically • G20210A mutation in prothrombin gene (general normal fetuses at or after the 10th week of gestation prevalence: 2%) • One or more premature births of morphologically • Antithrombin III deficiency (general prevalence: 1%) normal neonates at or before the 34th week of gesta- • Chronic myeloproliferative disorders tion (due to severe preeclampsia or severe placental • Behçet’s disease insufficiency) • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation (after the ex- clusion of anatomical and chromosomal abnormalities) thrombosis requires the use of thrombolytic drugs (as urokinase at the dose of 4400 IU/kg in bolus, to be continued at the dose of 4400 IU/kg/hour for at least 72 hours) imbricated with at a distance of 12 weeks to confirm APS diagno- intravenous standard heparin (at the dose of 50 sis22,23. The occurrence of thrombocytopenia, IU/kg in bolus, to be continued at the dose of 15- livedo reticularis and familiarity for autoimmune 20 IU/kg/hour when the thrombolytic drug is diseases (in particular for systemic lupus erythe- suspended) with the aim of doubling aPTT. He- matosus) increases the likelihood that APS can parin is indeed an efficacious anticoagulant drug be etiologically related to any thrombotic event. which interrupts thrombin activation and Tables V and VI show the permanent and tran- strengthens the role of antithrombin III. When sitory risks for venous thromboembolism. the thrombotic process is solving – as an altena- tive choice to standard heparin – it is possibile to use low-molecular-weight heparin (as enoxaparin at the dose of 100 U/kg every 12 hours), which Therapeutical/Prophylactic Strategies has a decreased risk of causing hemorrhages24. in the Anti-phospholipid Syndrome There is unanimous agreement about the necessi- ty of subjecting all children with APS to prophy- To estimate the risk of thrombotic complica- laxis in order to prevent thrombotic relapses. tions in APS is challenging as well as the ques- This requires the administration of oral anticoag- tions of which, how long and in what strength ulants, originally developed as rat poisons, acting anticoagulation is recommended. Different prac- by antagonizing the effect of vitamin K, resulting tices have been proposed for treatment and pro- in reduced hepatic production of active coagula- phylaxis of APS. Initially the management of tion factors II, VII, IX and X, and hence in pro-

Table IV. Laboratory criteria for the diagnosis of anti-phospholipid syndrome. Table VI. “Transitory” risk factors for venous thromboembolism. Positivity of lupus-like anticoagulant detected in the blood on two or more occasions at least 12 weeks • Surgical interventions apart •Traumatic injuries Positivity of anti-cardiolipin IgG and/or IgM antibodies •Prolonged immobilization present in moderate or high levels in the blood in two • “Economy class” syndrome or more occasions at least 12 weeks apart, measured • Infections and pyo-septic diseases on a standardized ELISA test •Pregnancy and puerpery β Positivity of anti- 2-glicoprotein I IgG and/or IgM • Antipsychotic medications antibodies present in moderate or high levels in the •Oral estroprogestinic formulations blood in two or more occasions at least 12 weeks •Nephrotic syndrome apart, measured on a standardized ELISA test • Systemic vasculitic syndrome

51 D. Rigante, S. Gaspari, G. Bersani, A. Stabile longation of the thromboplastin time expressed lins, although no controlled studies have docu- as international normalized ratio (or INR). Oral mented their efficacy27. Healthy subjects who oc- anticoagulants as warfarin and acenocoumarol casionally and accidentally result to have aPL in are prescribed at an individualized dose to the serum do not need to be treated with any sort achieve target INR between 2.0 and 3.025,26. They of therapy or prophylaxis28. usually take 48-72 hours to develop a full antico- With appropriate medication and lifestyle agulant effect, hence anticoagulation should be modifications most children with primary APS commenced with heparin in acute thromboem- can lead normal lives and reach adulthood with- bolism. Heparin is not required when oral antico- out problems. Only a minority of children with agulants are started electively for the prophylaxis secondary APS displays a severe course, often of thromboembolism and is contraindicated in leading to significant morbidity, though this cases of severe thrombocytopenia, history of he- might also be influenced by the underlying parin-induced thrombocytopenia, uncontrollable rheumatologic or autoimmune condition. active bleeding or when monitoring of platelets, hematocrit and stool for occult blood is not pos- sible. When warfarin is instituted it is of primary importance to instruct child’s parents to avoid ex- References cessive consumption of foods containing vitamin

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