- OVERVIEW: What every practitioner needs to know
Are you sure your patient has Antiphospholipid Syndrome? What are the typical findings for this disease?
- Diagnostic Criteria for the Antiphospholipid Syndrome
- Antiphospholipid antibodies
- Utility of testing for non-criteria aPL Ab
- Pathogenesis of the Antiphospholipid Syndrome
- Actions of Pathologic Antiphospholipid Antibodies
- Actions of Anti-beta-2 glycoprotein I Antibodies
- Criteria Clinical Manifestations of Pediatric APS
- Non-Criteria Clinical Manifestations Pediatric APS
What other disease/condition shares some of these symptoms?
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- If you are able to confirm that the patient has Antiphospholipid Syndrome, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
What is the evidence?
OVERVIEW: What every practitioner needs to know
Are you sure your patient has Antiphospholipid Syndrome? What are the typical findings for this disease?
The Antiphospholipid Syndrome (APS) is an acquired autoimmune disease that is characterized by vascular thrombosis and/or pregnancy morbidity in the setting of persistently elevated antiphospholipid antibodies (aPL Ab). Venous thrombosis is the most common manifestation of APS, occurring in over 60% of patients.
In pediatrics, APS is manifested as venous thrombosis or stroke, and can be accompanied by other findings such as thrombocytopenia, hemolytic anemia, or Raynaud's phenomenon. APS should be considered a systemic disease, and pediatricians of different specialties must be aware of pediatric APS and its heterogeneous presentation.
The incidence and prevalence of APS in pediatrics or adults is unknown.
The variety of clinical manifestations and the level of disease severity of pediatric APS are similar to what is seen in adults. Still, there are several characteristics that are unique to pediatric APS patients such as the paucity of common acquired prothrombotic risk factors (smoking, use of oral contraceptives, diabetes mellitus, etc) in this population.
Other differences include a high incidence of aPL Ab in otherwise healthy children versus healthy adults, and there is a prevalence of certain APS disease complications in pediatrics compared to adults. But, as APS is a rare syndrome in pediatrics and we lack prospective randomized trials, the diagnostic criteria, treatment modalities and prognosis of children with APS are often extrapolated from adult literature.
An important but rare subtype of APS is the Catastrophic Antiphospholipid Syndrome. It accounts for less than 1% of adult APS cases and is rare in pediatrics.
Primary APS versus Secondary APS
Previously, APS was classified as primary APS (PAPS) when the syndrome was idiopathic and unrelated to other disease while secondary APS was found in conjunction with other autoimmune disease, most often systemic lupus erythematosus (SLE). As clinical differences did not exist between primary and secondary APS, the 2006 revision of the Sapporo guidelines (Syndey criteria) recommended that the disorder associated with APS be listed (ie, "APS associated with SLE") rather than designating it as "secondary APS".
Yet, in an international multicenter cohort study of 121 pediatric APS cases certain differences were noted between APS and APS associated with autoimmune disease; approximately 50% of patients had APS associated with autoimmune disease, most commonly SLE. Of those patients with APS associated with autoimmune disease, the mean age of onset of symptoms was older, they were more likely to have hematologic manifestations, but less likely to have arterial thrombosis or ischemic stroke than children with APS alone.
Diagnostic Criteria for the Antiphospholipid Syndrome
The current diagnostic and research criteria for APS is based on the 2006 revised Sapporo guidelines which include both clinical and laboratory criteria. An individual must have one laboratory criteria and one clinical criteria to confirm the diagnosis of APS. Laboratory criteria must be positive on 2 or more occasions at least 12 weeks apart but within 5 years of clinical criteria. These criteria are currently applied to children, but no studies have validated these criteria in pediatric APS.
Vascular thrombosis in any venous or arterial bed, or in the microcirculation, affecting any organ or tissue and confirmed by imaging or histopathology. Histopathology commonly will not show evidence of vasculitis.
Pregnancy morbidity (of more value in adult patients)
One or more unexplained loss of a morphologically normal fetus (confirmed by ultrasound or direct examination) after the 10th week gestation
One or more premature births of a morphologically normal neonate before 34 weeks gestation due to pre-elampsia, eclampsia, or placental insufficiency
Three or more unexplained consecutive spontaneous abortions, excluding maternal anatomic or hormonal abnormalities, or chromosomal abnormalities
Lupus anticoagulant, as determined by prolongation of a phospholipid-dependent screening assay, evidence of inhibitory activity with mixing studies, evidence that the inhibitory activity is phospholipid dependent, and lack of specific inhibition of any one coagulation factor
Anti-cardiolipin IgM or IgG at moderate to high titer [>40 IgM or IgG phospholipid units (MPU, GPU) or greater than 99% of normal lab values] by standard ELISA
Anti-beta-2-glycoprotein 1 IgM or IgG at greater than 99% of normal lab values by standard ELISA
While these well-studied criteria are important in recognizing patients with APS, the clinician must also use her/his judgment in managing patients who may not meet the above strict histopathologic or imaging criteria. While the diagnosis of APS is absolutely dependent on positive aPL Ab testing, healthy children have a high incidence of positive aPL Ab testing, therefore not all children with aPL Ab have APS.
Also, non-criteria findings suggestive of APS may be significant in narrowing down a diagnosis of APS. The clinician must therefore decide whether these tests are related to the clinical event. Often, repeat testing in convalescence can help guide diagnosis and therapy, as well a thorough past and family history, particularly inquiring about autoimmunity.
Seronegative APS (SNAPS) is a controversial entity. SNAPS is defined as a syndrome demonstrating typical clinical findings of APS without any of the criteria laboratory findings. For such patients, the clinician should repeat aPL Ab testing on multiple occasions, as testing cannot always be reliable, especially during an acute thrombotic event (due to possible consumption of antibodies). Without any evidence of aPL Ab, a broad differential diagnosis must be explored.
Antiphospholipid antibodies (aPL Ab) are a functionally and immunologically heterogeneous group of immunoglobulins that recognize a variety of phospholipid-binding proteins, phospholipid-protein complexes, or phospholipids. Not all aPL Ab are associated with the Antiphospholipid Syndrome. Approximately 2-10% of healthy children will have positive aPL Ab testing, and the levels of aPL Ab increases with age, with asymptomatic individuals greater than 60 years having higher baseline levels of aPL Ab.
While only anti-beta-2-glycoprotein I (anti-B2GPI) antibodies and anti-cardiolipin antibodies (which may or may not be beta-2-glycoprotein I dependent) are a part of the diagnostic criteria of APS, many other aPL Ab exist. Controversy exists regarding which of these other aPL Ab are clinically relevant to the manifestations of APS. Non-criteria aPL Abs include anti-phosphatidylserine, anti-phosphatidylethanolamine, anti-prothrombin, anti-annexin V, anti-protein C, anti-protein S, among others. Anti-prothrombin aPL Abs can result in a separate syndrome, the Lupus Anticoagulant-Hypoprothrombinemia syndrome (see further discussion of this under "APL Ab and other conditions").
Utility of testing for non-criteria aPL Ab
As discussed, aPL Ab encompass a wide range of antibodies, and it remains to be shown whether testing for these non-criteria aPL Ab is useful in diagnosing or managing APS patient. The International Congress on Antiphospholipid Antibodies met in April 2010, and the following summarizes the difficulties in adding these antibodies as APS criteria.
Anti-phosphatidylethanolamine antibodies(anti-PE) have been described in some reports as the sole aPL Ab in patients with clinical manifestations of APS, including women with obstetrical complications and individuals with venous thrombosis. No standardized method exists for the measurement of anti-PE, limiting the clinical utility of this assay. Well-designed clinical studies are needed prior to the addition of this test under APS criteria laboratory findings.
Anti-cardiolipin IgA antibodies have been shown in several studies to be associated with recurrent fetal loss and thrombosis, and in cases of suspected APS with negative aCL IgG or IgM, aCL IgA may be useful. Assays for testing are not standardized, though, and antibody levels can have ethnic variability.
Anti-B2GPI IgA antibodies have been associated with clinical manifestations of APS, and have also been associated with acute myocardial infarctions in populations without APS. Isolated IgA anti-B2GPI antibody titers may be used to identify additional patients who have negative laboratory criteria for APS but who have clinical features of APS.
Anti-prothrombin antibodies can bind to prothrombin (aPT-A) and to prothrombin bound to phosphatidylserine (aPS-PT), and studies have been conflicting with regard to the relationship of these antibodies to APS-related clinical features, although more recent prospective studies show an association between these antibodies and first episode of thrombosis. Planning for a multi-center study by the International Congress on Antiphospholipid Antibodies is underway.
Anti-phosphatidylserine (anti-PS) antibodieshave been studied in thrombosis and pregnancy related morbidity in APS, and may be more specific than anti-cardiolipin antibodies (as aCL Ab are found in other conditions) for these conditions. It is unclear whether the addition of ant-PS Ab testing is of value, though, as anti-PS Ab are often found in conjunction with aCL Ab and anti-PS Ab in isolation show questionable clinical relevance. Assays for anti-PS antibodies also lack standardization and reproducibility between manufacturers.
Pathogenesis of the Antiphospholipid Syndrome
The mechanism of pathologic antiphospholipid antibody formation has not yet been elucidated. One common theory suggests that infection may act as "polyclonal activators" of lymphocyte subsets or trigger an autoimmune response to plasma proteins possibly through molecular mimicry, specifically targeting beta-2-glycoprotien I. These antibodies in conjunction with a "second hit" phenomenon or host predisposition may allow these circulating antibodies to target endothelial cells, monocytes, platelets and trophoblasts, resulting in the clinical phenotype of APS.
While there are no known causative genes for APS, certain HLA II alleles have been more commonly reported in patients with APS, and gene expression patterns have been shown to predict APS in patients with venous thrombosis. Although APS is the most common acquired thrombophilia, several cases of familial APS have been reported, suggesting an autosomal dominant inheritance in this small group of patients.
Actions of Pathologic Antiphospholipid Antibodies
As APS is a heterogeneous disease, it is believed that there are several distinct pathologic mechanisms at play. Theories of aPL Ab actions include:
Cellular activation(endothelium, monocytes, platelets, trophoblasts)
In vitro and in vivo studies have shown that aPL Ab activate endothelial cells and monocytes resulting in increased expression of adhesion molecules such as VCAM-1, ICAM-1, and tissue factor. Exposure of endothelial cells or monocytes to aPL Ab also results in increased cytokine release
Cell surface receptors implicated in the aPL Ab-induced signal transduction in target cells are the toll-like receptor 4 and apolipoprotein E receptor 2 (apoER2).
Activation of complement
Evidence has shown that aPL Ab effects on murine models of pregnancy outcomes is complement-dependent, and the protective heparin in these models is due to heparin's effect on complement.
Inhibition of natural anticoagulants
Anti-protein C and anti-protein S antibodies that inhibit function of this axis in vitro
APL Ab against annexin A5 are thought to disrupt this anticoagulant shield on endothelium and placental villi.
Inhibition of fibrinolysis
Inhibition of plasmin by B2GPI antibodies
Actions of Anti-beta-2 glycoprotein I Antibodies
Beta-2 glycoprotein I (B2GPI) is a major antigenic target for aPL Ab. While B2GPI postulated to function as a natural anticoagulant, it's physiologic role is unknown, and both humans and mice lacking B2GPI do not have a thrombotic phenotype. As such, aPL Ab may cause B2GPI to take on a new pathologic role in APS. Antibodies against beta-2 glycoprotein I and its complexes with cardiolipin account for most of the positive anticardiolipid antibodies.
Anti-B2GPI Ab are heterogeneous and can be directed towards different epitopes on different domains of the B2GPI molecule. Work by several investigators have elucidated the important role of domain I of B2GPI as the primary epitope for aPL Ab. De Laat and colleagues found that anti-domain I B2GPI antibodies associated more strongly with thrombosis and obstetric complications than anti-B2GPI Ab detected by conventional assays.
It is postulated that B2GPI binds to exposed phospholipid at times of tissue injury ("second hit") resulting in a conformational change in structure, exposing a cryptic epitope on domain I of B2PGI. Pathologic aPL Ab can then bind to this site. The mechanism by which binding of aPL Ab result in the varied clinical manifestations is still being elucidated.
Criteria Clinical Manifestations of Pediatric APS
Thrombosis is the primary manifestation of APS in children and adolescents. Obstetric complications associated with APS are obviously less common in pediatrics. Pediatric patients can present with venous, arterial or mixed arterial/venous thrombosis. In both pediatric and adult patients, a lupus anticoagulant is the strongest predictor of the risk of thromboembolic events.
Venous thrombosis including:
Deep vein thrombosis in lower extremities are most common
Large vessel thrombosis involving the inferior vena cava
Budd-Chiari syndrome, which is thrombosis occluding the inferior vena cava and extending to the hepatic veins
Portal vein thrombosis
Cerebral venous sinus thrombosis
Cerebral infarctions are the most common arterial events in pediatric APS, most often in the territory of the middle cerebral artery
Transient ischemic attacks (TIA) including transient parasthesias, motor weakness, vertigo, and amaurosis fugax
Peripheral artery occlusion
Retinal artery occlusion
Renal artery thrombosis
Adrenal gland infarction
Renal thrombotic microangiopathy
May be difficult to distinguish from other microangiopathic conditions such as TTP or HUS
Non-Criteria Clinical Manifestations Pediatric APS
At this time, there is not sufficient evidence to use non-thrombotic or non-obstetric clinical features as criteria for the diagnosis of the Antiphospholipid Syndrome. Nonetheless, aPL Ab may cause additional non-criteria clinical manifestations, that when observed in a child or adolescent with unprovoked thrombosis, should lead one to consider APS as a diagnosis. In the absence of thrombotic (or obstetric) events, these symptoms may be classified as "antiphospholipid antibody-associated `X'" if the requisite highly elevated levels of aPL Ab are present and there is no other etiology.
Hematologic involvement occurs in approximately 38% of pediatric APS patients
Mild to moderate thrombocytopenia. Pathogenesis of thrombocytopenia is considered to be multifactorial, including immune clearance of platelets due to binding by aCL antibodies and antibodies to platelet glycoproteins. There may also be a component of aPL-Ab induced platelet aggregation inducing mild thrombocytopenia. Many investigators feel that fhrombocytopenia has strong evidence for incorporation into the clinical criteria of APS.
Hemolytic anemia has also been reported in APS, often autoimmune in nature, but occasionally associated with microangiopathic hemolysis.
Skin involvement, most often attributed to vascular occlusion, is seen in approximately 18% of pediatric APS cases.
Livedo reticularis is the most frequently associated skin manifestation of APS. It is defined as the persistent violacious reticular or mottled pattern of the skin of the trunk or extremities, not reversible with warming of the skin. This is more common in patients with APS associated with SLE. Livedo reticularis can progress to tissue ischemia, cutaneous nodules, and/or ulcerations.
Raynaud's phenomenon- vasoconstriction of the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts resulting in tissue ischemia. Often involves the finger, toes, but can affect nose, ears as well
Central nervous system involvement (non-thrombotic) occurs in approximately 16% of children with APS.
Left-sided cardiac valve thickening and vegetations, the mitral valve most commonly involved
Rarely, myocardial infarction
Pulmonary hypertension related to microthromboembolic events
Endocrine involvement has also been reported, specifically adrenal insufficiency due to infarction of adrenal gland
What other disease/condition shares some of these symptoms?
The differential diagnosis of the antiphospholipid syndrome can be wide, depending on the clinical manifestations. Included in this differential are the following:
Heritable thrombophilia such as Factor V Leiden, prothrombin G20210A mutation, congenital antithrombin, protein C, or protein S deficiency
Infections such as varicella (acquired, transient anti-Protein S autoantibodies)
Microangiopathic hemolytic anemia syndromes such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
For any pediatric patient that presents with a new spontaneous venous thromboembolic event or arterial thrombosis suspected of having APS, the following labs should be considered:
Complete blood count with platelets
Heritable thrombophilia testing, if indicated
Prothrombin time (PT) and activated prothromboplastin time (aPTT), D-Dimer
lupus anticoagulant testing: aPTT, dilute Russell viper venom time (dRVVT), kaolin clotting time (KCT), anti-cardiolipin antibodies, anti-beta-2 glycoprotein I antibodies
If you are able to confirm that the patient has Antiphospholipid Syndrome, what treatment should be initiated?
The mainstay of therapy for thrombotic events in pediatric APS is anticoagulation. Pediatric APS-associated venous or arterial thrombosis should be managed as other non-aPL Ab associated thrombosis, using standardized published treatment guidelines (Monagle et al, Chest 2008). The optimal duration and intensity of anticoagulation in pediatric APS is unknown.
Treatment of venous thrombosis
Unfractionated heparin or low molecular weight heparin. Goal LMWH anti-Xa levels of 0.5-1. For patients started on unfractionated heparin during initial hospitalization, UF anti-Xa levels should be monitored for patients with baseline elevated aPTT (goal of 0.35-0.7.)
Warfarin at INR 2-3. Heparin bridging to warfarin is strongly recommended
It is not recommended to use newer agents such as direct thrombin inhibitors (except for suspected HIT) or anti-Xa inhibitors in pediatrics outside of a clinical trial
Compression stockings (20-30mm Hg) are recommended for lower extremity and some upper extremity DVTs
Duration of therapy
Consider a minimum of 3-6 months of therapy if there were predisposing risk factors (venous catheter, estrogen-containing contraceptives, immobilization, etc) that have resolved, and/or there is no longer persistence of aPL Ab
Patients with no predisposing factors likely require long-term therapeutic anticoagulation
Whether prophylactic anticoagulation after initial treatment doses decreases thrombotic recurrences is unknown
The risks and benefits of continued anticoagulation in children and adolescents should be reassessed at regular intervals
Treatment of arterial thrombosis
Medical therapy of stroke/TIA should be based on current guidelines (Monagle et al Chest 2008)
Anticoagulation if cardioembolic or arterial dissection
As with other children with idiopathic stroke, a cardiac ECHO should be performed to rule out an intra-cardiac shunt
Acute stroke in older adolescents may be treated per adult American Heart Association guidelines, with systemic thrombolysis if indicated
Aspirin 1-5 mg/kg/day for a minimum of 2 years, regardless of aPL Ab persistence
Medical therapy of non-cerebral thrombosis can include anticoagulation with heparin for 5-7 days, aspirin, or systemic thrombolysis if limb or life-threatening arterial thrombosis occurs.
Patients with APS should be counseled about the risks of secondary provoking factors of thrombosis such as immobilization, tobacco smoke (especially in adolescents), estrogen use in females, obesity and hypertension.
Early intervention with diet modification, exercise or antihypertensives are equally important in the management of these patients.
Risk of Recurrent Thrombosis
Approximately 20% of pediatric APS patients will develop recurrent thrombosis, often in similar vessel type as their initial event. The risk of recurrence is higher after the first 6 months of cessation of anticoagulant therapy. Double or triple positivity (lupus anticoagulant, anti-cardiolipin antibodies, and anti-beta-2 glycoprotein I antibodies) likely increase the risk recurrent thrombotic events. Because of this, long-term anticoagulation may be warranted.
Management of Non-criteria Manifestations
There is a lack of prospective randomized controlled trials to guide our treatment of pediatric APS. In adults, there is currently no evidence that anticoagulation is effective therapy for non-thrombotic complications of APS. Current recommendations are to treat these manifestations with symptom-specific therapies, such as IVIG or steroids for symptomatic thrombocytopenia, calcium channel blockers for Raynaud's phenomenon, or low dose aspirin for cardiac valve abnormalities.
While hydroxychloroquine has been used in SLE patients with similar manifestations, the use of hydroxychloroquine in pediatric APS has not been studied and cannot be recommended at this time.
Individuals may present with persistently positive lupus anticoagulant or aPL Ab at moderate to high titers and non-criteria clinical manifestations of APS in the absence of thrombosis. A percentage of these children may go on to develop vascular thrombosis, but there is no data to support anticoagulation for these patients as primary prophylaxis.
Current recommendations include frequent monitoring of patients for manifestations of systemic autoimmune disease or for tight control of known autoimmune disease. Any secondary risk factors for thrombosis should be addressed and treated if possible. Prophylactic doses of anticoagulation should be considered in situations that places these patients at high risk for thrombosis such as immobilization or nephrotic syndrome. Patients and families must also receive education and counseling regarding possible procoagulant risks and lifestyle changes.
The use of aspirin as primary prophylaxis was shown not to be of benefit in a randomized controlled trial in adults with aPL Ab and non-criteria manifestations of APS. In children, studies are lacking, and current recommendations are not to treat with aspirin due to the risk of bleeding in an active child, but this should be addressed on a case by case basis. Hydroxychloroquine for primary prophylaxis in individuals with aPL Ab without SLE has not been studied and, therefore, is currently not recommended.
The Catastrophic Antiphospholipid Syndrome
The catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening subtype of APS that requires a high index of suspicion for diagnosis and aggressive therapy. CAPS is characterized by multiple small vessel thrombi that can lead to multi-organ failure, and the disease process can be acute or evolving over 1 week.
CAPS is a thrombotic microangiopathy with a predilection for the kidney, brain, lung, skin, heart, and gastrointestinal tract, and its presentation can often mimic that of other thrombotic micoangiopathies such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), or heparin-induced thrombocytopenia (HIT). The kidney is the most commonly affected organ in CAPS, and often patients present with hypertension or acute renal failure.
Predisposing factors for this thrombotic microangiopathy include infection, surgery, autoimmune disease flare, withdrawal of warfarin therapy, or estrogen therapy. Patients can also present without a known inciting event. In adults, mortality is estimated to be 30-50%, but pediatric data is not available due to the rarity of the disease.
Diagnostic Criteria for the Catastrophic Antiphospholipid Syndrome
Criteria for the diagnosis of CAPS includes:
Evidence of thrombosis in three or moreorgans, systems, or tissues
Clinical evidence of vessel occlusion confirmed by imaging when available/appropriate
Histopathologic confirmation should show significant evidence of thrombosis without or without co-existing vasculitis
50% rise in serum creatinine, systemic hypertension greater than 180/100 mm Hg, and/or proteinuria (>500mg/24hrs) constitute renal involvement
Development of manifestations simultaneously or less than one week
Confirmation by histopathology of small vessel occlusion in at least one organ or tissue
Laboratory confirmation of aPL Ab, per APS criteria
The diagnosis of definite CAPS meets all four criteria above.
Probable CAPS diagnosis can fall under the following categories:
All four criteria (above) except for only 2 organs, systems, and/or tissues involved
All four criteria (above) except for the absence of laboratory confirmation 12 weeks apart due to the early death of a patient not tested for aPL Ab prior to CAPS
Criteria 1, 2, 4
Criteria 1, 3, 4 and the development of a third event in more than a week but less than a month despite anticoagulation
Treatment of Catastrophic Antiphospholipid Syndrome
The optimal treatment regimen for CAPS is unknown, and there are no prospective randomized trials investigating different treatment regimens in this disorder. In an analysis of 250 patients in the CAPS registry (European Forum on Antiphospholipid Antibodies), an association with higher recovery rate was shown with combined treatment with anticoagulants plus corticosteroids plus plasma exchange.
Recommended therapy for pediatric patients with CAPS is based on adult reports, clinical, and anecdotal experience. The following treatment regimen should be considered in a suspected case of pediatric CAPS:
Therapeutic anticoagulation with unfractionated heparin, with transition to oral vitamin K antagonists if appropriate
High dose corticosteroids, tapering the dose when stable
Plasmapheresis with fresh frozen plasma replacement (preferred to albumin replacement)
Consideration of intravenous immunoglobulin (IVIG)
Treatment of any inciting event (infection, SLE flare, etc.)
Occasionally, immumodulatory therapy with rituximab can be of benefit
Antiphospholipid Antibodies in Other Conditions
Transient aPL Ab in asymptomatic children
In otherwise healthy, asymptomatic children, antiphospholipid antibodies do not usually result in clinical manifestations. These aPL Ab are often post-infectious or idiopathic antibodies that are transient and result in a prolongation of the activated prothromboplastin time (aPTT). This abnormal testing is often discovered in pre-surgical screening in young children.
Most studies evaluating aPL Ab in "normal" children estimate the prevalence of these antibodies to be between 2-10%.
It has been postulated that differences in pediatric developmental hemostasis, lack of risk factors for thrombosis (obesity, hypertension, diabetes mellitus, smoking, etc), healthier endothelium, and the transience of the antibodies account for the lack of thrombosis in this population.
In one retrospective study of 95 children with a median age of 5.3 years and a positive lupus anticoagulant, 85% were asymptomatic at diagnosis and remained asymptomatic. In a German study looking a children without autoimmune disease, 89% (n=54) of children with symptomatic infection had at least one aPl Ab, while 13% (n=38) of healthy controls had a positive lupus anticoagulant.
Lupus Anticoagulant-Hypoprothrombinemia Syndrome
This syndrome is a transient hemorrhagic diathesis in a previously healthy child with a positive lupus anticoagulant, a prolonged prothrombin time (PT) and a prolonged activated prothromboplastin time (aPTT). It is due to acquired prothrombin-binding antibodies, which are non-neutralizing but form antigen-antibody complexes that results in decreases in circulating prothrombin and is often preceded by a viral infection.
One study of 95 children with a positive lupus anticoagulant showed that 8% of patients had severe, transient hypoprothrombinemia, only 5 of these 8 children had bleeding manifestations, and factor II levels normalized within 2 to 7 weeks in all patients.
For significant bleeding manifestations, corticosteroid therapy is recommended
Neonates of Mothers with APS
The transplacental transfer of aPL Ab occurs in infants born to mother with the Antiphospholipid Syndrome, and as expected, these antibodies are undetectable by 6 months of age.
Aside from prematurity related to maternal APS, most infants do not exhibit clinical manifestations of APS, and there is currently no data to suggest neurocognitive problems later in childhood. There are case reports, though, of aPL Ab-associated thrombosis in neonates of mothers with APS, therefore these infants should be monitored for any signs suggestive of a thrombotic event.
Drug and Malignancy Associated-aPL Ab
APL Ab associated with drugs and malignancy have been reported in adult patients, but little data exists in pediatrics. Malignancies associated with aPL Ab in adults have ranged from carcinomas to hematologic malignancies. Several drugs that are associated with lupus-like syndromes such as thiazide diuretics and minocycline can also result in detectable aPL Ab.
What are the adverse effects associated with each treatment option?
The highest risk of anticoagulation in pediatrics is bleeding, regardless of whether heparins, vitamin K antagonists or antiplatelet medications are used. Agent specific side effects include:
Heparin induced thrombocytopenia (HIT)
Mild alopecia with long term use
Osteopenia with long term use
Hypersensitivity skin reactions
Local irritation and pain with subcutaneous injections
Drug and diet interactions
Skin necrosis, especially if bridging heparin therapy is not used
Allergic reactions, including anaphylaxis
Reye's syndrome in children with varicella, influenza or other viral infections
Treatment failure has been reported in patients with APS on therapeutic anticoagulation. Management of such instances can include increasing the intensity of anticoagulation, changing from warfarin to heparin or heparin to warfarin, or the addition of anti-platelet therapy to anticoagulation. New agents hold promise for improved therapeutic options in pediatrics.
What is the evidence?
Angelini, L, Ravelli, A, Caporali, R, Rumi, V. "High prevalence of antiphospholipid antibodies in children with idiopathic cerebral ischemia". Pediatrics. vol. 94. 1994. pp. 500-3.(Prevalence of aPL Ab in a case series of 13 patients with stroke or TIA.)
Avcin, T, Cimaz, R, Silverman, ED. "Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry". Pediatrics. vol. 122. 2008. pp. e1100-7.(Multicenter, international bidirectional cohort study of pediatric APS identified using revised Sapporo criteria; to date the largest number of pediatric APS cases published.)
Barbhaiya, M, Erkan, D. "Primary thrombosis prophylaxis in antiphospholipid antibody-positive patients: where do we stand?". Curr Rheum Rep. vol. 13. 2011. pp. 59-69.
Bernard, TJ, Goldenberg, NA, Armstrong-Wells, J. "Treatment of childhood arterial ischemic stroke". Ann Neurol. vol. 63. 2008. pp. 679-96.
Bertolaccini, ML, Amengual, O, Atsumi, T. ""Non-criteria" aPL test: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010". Lupus. vol. 20. 2010. pp. 191-205.
Bucciarelli, S, Espinosa, G, Cervera, R. "Mortality in the catastrophic antiphospholipid syndrome: cause of death and prognostic factors in a series of 250 patients". Arthritis & Rheum. vol. 54. 2006. pp. 2568-76.
Cervera, R, Bucciarelli, S, Plastin, MA. "Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of a series of 280 patients from the "CAPS Registry"". Journal of Autoimmunity. vol. 32. 2009. pp. 240-5.
Cervera, R. "Catastrophic antiphospholipid syndrome (CAPS): update from the "CAPS Registry"". Lupus. vol. 19. 2010. pp. 412-8.
Cimaz, R, Descloux, E. "Pediatric antiphospholipid syndrome". Rheum Dis Clin. vol. 32. 2006. pp. 553-73.(Excellent review of pediatric APS.)
Crowther, MA, Ginsberg, JA, Julian, J. "A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome". N Eng J Med.. vol. 349. 2003. pp. 1133-8.
Erkan, D, Harrison, MJ, Levy, R. "Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals". Arthritis Rheum. vol. 56. 2007. pp. 2382-91.(Randomized controlled trial in adults that showed no benefit to aspirin therapy versus placebo in adults with persistently postive aPL Ab.)
Falcini, R, Taccetti, G, Ermini, M. "Catastrophic antiphospholipid antibody syndrome in pediatric systemic lupus erythematosus". J Rheumatol. vol. 24. 1997. pp. 389-92.
Frauenkneckt, K, Lackner, K, von Landenberg, P. "Antiphospholiid antibodies in pediatric patients with prolonged activated partial thromboplastin time during infection". Immunobiology. vol. 210. 2005. pp. 799-805.(A study evaluating presence of aPL Ab in children with and without infection and without autoimmune disease.)
Gattorno, M, Falcini, F, Ravelli, A. "Outcome of primary antiphospholipid syndrome in childhood". Lupus. vol. 12. 2003. pp. 449-53.
Giannakopoulos, B, Krilis, SA. "How I treat the antiphospholipid syndrome". Blood. vol. 114. 2009. pp. 2020-30.(Expert opinion on the management of APS in adults.)
Girardi, G, Berman, J, Redecha, P. "Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome". J Clin Invest. vol. 112. 2003. pp. 1644-54.
Iglesias-Jimenez, E, Camacho-Lovillo, M, Falcon-Neyra, D. "Infant with probable catastrophic antiphospholipid syndrome successfully treated with rituximab". Pediatrics. vol. 125. 2010. pp. e1523-8.
Male, C, Foulon, D, Hoogendoorn, H. "Predictive value of persistent versus transient antiphopholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus". Blood. vol. 106. 2005. pp. 4152-8.(This is an ambidirectional cohort study of children with SLE that demonstrated a persistent lupus anticoagulant is the strongest predictor of risk for thromboembolism.)
Male, C, Lechner, K, Eichinger, S. "Clinical significance of lupus anticoagulants in children". J Peds. vol. 134. 1999. pp. 199-205.(A retrospective review of 95 consecutive children with a positive lupus anticoagulant, providing evidence that the majority of lupus anticoagulants in children are transient and do not have clinical manifestations.)
Miyakis, S. "International consensus statement on an update of the classification criteria for definite antisphospholipid syndrome (APS)". J Thromb Haemost. vol. 4. 2006. pp. 295-306.(This is the most current revision of the initial Sapporo guidelines for the classification of APS.)
Monagle, P, Chalmers, E, Chan, A. "Antithrombotic therapy in neonates and children: American College of Chest Physicians evidence-based clinical practice guidelines". Chest. vol. 133. 2008. pp. 887s-968s.(Evidence based guidelines on the treatment of thrombotic events in children.)
Park, JM, Shin, JI, Shin, YH. "Catastrophic antiphospholipid syndrome in a 7-year-old girl". Clin Rheumatol. vol. 26. 2007. pp. 1011-3.
Pierangeli, SS, Vega-Ostertag, ME, Raschi, E. "Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies". Ann Rheum Dis. vol. 66. 2007. pp. 1327-33.
Ramesh, S, Morrell, CN, Tarango, C. "Antiphospholipid antibodies promote leukocyte-endothelial adhesion and thormbosis in mice by antagonizing eNOS via beta-2FPI and apoER2". J Clin Invest.. vol. 121. 2011. pp. 120-31.
Rand, JH, Wu, XX, Andree, HAM, Ross, JBA. "Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a "lupus procoagulant" phenomenon". Blood. vol. 92. 1998. pp. 1652-60.
Ravelli, A, Martini, A. "Antiphospholipid antibody syndrome in pediatric patients". Rheum Dis Clin. vol. 23. 1997. pp. 657-76.(Early case series of pediatric APS with a review of clinical manifestation.)
Ruffati, A, Del Ross, T, Ciprian, M. "Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study". Ann Rheum Dis. vol. 70. 2011. pp. 1083-6.(Prospective observational study of 258 adult patients with aPL Ab where hypertension and lupus anticoagulant were independent risk factors for thrombosis.)
Tripodi, A, de Groot, PG, Pengo, V. "Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment". J Intl Med. vol. 270. 2011. pp. 110-22.(Current, insightful review of APS discussing methods of laboratory testing, pathophysiology.)
von Scheven, E, Athreya, BH, Rose, CD. "Clinical characteristics of antiphospholipid antibody syndrome in children". J Peds. vol. 129. 1996. pp. 339-44.
Wong, RCW, Favaloro, EJ. "Clinical features, diagnosis, and management of the antiphospholipid syndrome". Semin Thromb Hemost. vol. 32. 2008. pp. 295-304.(Current review of adult APS.)
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