Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune multisystem disease primarily manifested as intravascular thrombosis and mediated by antiphospholipid antibodies (APLA). APS may occur as an isolated clinical entity (primary APS) or in association with other autoimmune diseases (secondary APS), particularly systemic lupus erythematosus (SLE). It occasionally occurs with infections and malignancies as well. Rarely, patients develop catastrophic antiphospholipid syndrome (CAPS), a life- and organ-threatening condition in which microthrombi throughout the circulation cause multiorgan system dysfunction in the setting of systemic inflammatory activation and APLA.

Definition and Classification

The term APS refers to patients presenting with vascular thrombosis or recurrent fetal losses associated with the presence of APLA, for example, the lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β ₂ glycoprotein I antibodies (anti-β ₂ GPI) of immunoglobulin G (IgG) and/or IgM isotype detected on two or more occasions at least 12 weeks apart ( Table 24.1 ). The current APS classification criteria were evaluated only in studies in adults and do not include many heterogeneous manifestations associated with the presence of APLA, such as livedo reticularis, thrombocytopenia, or heart valve disease.

Table 24.1

Revised Criteria for the Classification of Antiphospholipid Syndrome

APS is present if at least one of the clinical criteria and one of the laboratory criteria are met.

Clinical criteria:

1.
Vascular thrombosis
One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.
2.
Pregnancy morbidity
- (a)
  One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus.
- (b)
  One or more premature births of a morphologically normal neonate before the 34th week of gestation because of (1) eclampsia or severe preeclampsia defined according to standard definitions or (2) recognized features of placental insufficiency.
- (c)
  Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomical or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Laboratory criteria:

1.
LA present in plasma on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis.
2.
Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e., >40 GPL or MPL, or > the 99th percentile) on two or more occasions at least 12 weeks apart, and measured by a standardized ELISA.
3.
Anti-β ₂ glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titer > the 99th percentile), present on two or more occasions at least 12 weeks apart, and measured by a standardized ELISA.

APS, Antiphospholipid syndrome; ELISA, enzyme-linked immunosorbent assay; GPL, IgG phospholipid units; Ig, immunoglobulin; LA, lupus anticoagulant; MPL, IgM phospholipid units.

Pediatric APS refers to patients in whom the onset of APS is prior to age 18 years. APS in children presents primarily as vascular thromboses and less frequently as isolated neurological or hematological disease. ^, Pregnancy morbidity, one of the two clinical criteria for definite APS in adults, is usually not seen in children, and it is possible that current consensus criteria may fail to recognize a subgroup of pediatric patients with APS who do not have vascular thrombosis but demonstrate typical nonthrombotic clinical features and fulfill the laboratory criteria for APS. ^, A classification of probable APS has been given to patients with APLA who have clinical features other than thromboses, which are associated with APLA, such as unexplained thrombocytopenia, livedo reticularis, heart valve disease, renal thrombotic microangiopathy, and neurological manifestations. ^,

Seronegative APS is a term used for patients with clinical manifestations highly suggestive of APS, but who have consistently negative results in the assays for aCL, anti-β ₂ GPI, and LA. ^, Some of these patients may have “noncriteria” APLA including antibodies to phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, and phospholipid-binding plasma proteins (prothrombin, protein C, protein S, annexin V, and domains of β ₂ GPI—currently research tests only). The clinical relevance of noncriteria APLA remains controversial; however, some of the new APLA assays may be added as laboratory diagnostic markers in future revisions of classification criteria for APS. The strongest association with thrombotic events was demonstrated for antiphosphatidylserine/prothrombin antibodies (aPS/PT) and antibodies to domain I of β ₂ -glycoprotein I. ^,

CAPS is an important subset of APS characterized by widespread thrombotic disease with multiorgan failure and a high mortality rate. This syndrome involves thrombotic damage in at least three organ systems or tissues over less than a week with histopathologic evidence of microthrombosis and laboratory confirmation of the presence of APLA ( Box 24.1 ). ^, Thromboses in CAPS typically affect small blood vessels, but large vessel occlusions can also occur. ^, Other causes of widespread thrombosis such as disseminated intravascular coagulation, heparin-induced thrombocytopenia, or thrombotic microangiopathy must be considered.

BOX 24.1

Preliminary Criteria for the Classification of Catastrophic Antiphospholipid Syndrome

Modified from Asherson RA, Cervera R, de Groot PG et al: Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus . 12:530-534, 2003.

APLA, Antiphospholipid antibodies; APS, antiphospholipid syndrome.

1.
Evidence of involvement of three or more organs, systems, and/or tissues
2.
Development of manifestations simultaneous or in less than a week
3.
Confirmation by histopathology of small-vessel occlusion in at least one organ or tissue
4.
Laboratory confirmation of the presence of antiphospholipid antibodies

Definite Catastrophic APS

All four criteria

Probable Catastrophic APS

All four criteria except for only two organs, systems, and/or tissues involvement
All four criteria except for the absence of laboratory confirmation at least 6 weeks apart because of the early death of a patient never tested for APLA before the catastrophic APS
1, 2, and 4
1, 3, and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation

Epidemiology

APS is the most common acquired prothrombotic autoimmune disease. It has an estimated incidence of 2 to 5 cases per 100,000 adults per year, and a prevalence of 40 to 50 cases per 100,000 adults. A cumulative retrospective analysis shows that one in three patients with APLA has a history of thrombosis. ^, ^, Based on a large meta-analysis in adult populations, the estimated prevalence of APLA in deep venous thrombosis was 9.5%, in stroke 13.5%, in myocardial infarction 11%, and in pregnancy morbidity 6%.

There are no reliable data on the incidence or prevalence of APS in the pediatric population and the diagnosis rests on the application of adult guidelines and clinical judgment. In a cohort study of 1000 consecutive patients with APS from 13 European countries, 85% of patients were diagnosed between ages 15 and 50 years. Those with disease before age 15 accounted for 2.8% of patients with APS. Although thrombosis in children is much less common than in adults, the proportion of thrombosis that is attributable to APLA in children is higher than in adults, who have other common prothrombotic risk factors such as atherosclerosis, smoking, hypertension, and use of oral contraceptives. The prevalence of APLA in unselected children with thrombosis is between 12% and 25%. ^, Meta-analysis of 16 observational studies investigating the association of APLA and first onset of thromboembolism in children showed persistent APLA positivity in 1% to 22% of arterial and 2% to 12% of venous thrombotic events.

The demographic characteristics of 121 children with APLA-related thrombosis in an international registry of pediatric APS revealed a mean age at disease onset of 10.7 years (range 1.0 to 17.9 years). There is a moderate female predominance in pediatric APS with girls outnumbering boys between 1.2:1 and 3:1. In adults the female-to male ratio exceeds 5:1. ^, ^, This difference may reflect sampling bias, as adult APS studies included patients with pregnancy morbidity and thrombosis. Very little is known about the geographical and racial distribution of pediatric APS.

Primary Antiphospholipid Syndrome

Primary APS without identified underlying disease accounts for 25% to 50% of pediatric patients with APS. ^, ^, This percentage may be somewhat overestimated because a number of children initially present with primary APS and later during the follow-up develop overt SLE. ^, ^, During the 6.1-year mean follow-up period, 21% of children who were initially diagnosed with primary APS progressed to have either definite SLE or lupus-like disease. Comparisons between children with primary APS and those with APS associated with underlying autoimmune disease suggest that children with primary APS are younger and have a higher frequency of arterial thromboses, especially cerebrovascular ischemic events. In contrast, children with APS associated with underlying autoimmune disease have a higher frequency of venous thrombotic events and hematological or skin manifestations.

Secondary Antiphospholipid Syndrome

Autoimmune Diseases

From the pediatric APS registry data, 50% to 70% of cases of APS in children are associated with an underlying autoimmune disease. ^, ^, There are only limited data addressing how autoimmune disease modifies the expression of APS, and sometimes the clinical distinction between primary APS and APS associated with an autoimmune disease is difficult, particularly in SLE, where many lupus features overlap with APS, including thrombocytopenia, hemolytic anemia, seizures, and proteinuria.

SLE and lupus-like disease account for the majority (80% to 90%) of pediatric APS cases associated with underlying autoimmune disease. ^, SLE is the autoimmune disease in which APLA can be found most often, with reported APLA frequencies ranging from 19% to 87% for aCL, 27% to 48% for anti-β2GPI, and 10% to 62% for LA, respectively. A meta-analysis of published studies examining APLA in childhood-onset SLE showed a global prevalence of 44% for aCL, 40% for anti-β ₂ GPI, and 22% for LA.

Children with juvenile idiopathic arthritis (JIA) have a high rate of APLA but very rarely develop APLA-related thrombotic events. ^, Whereas aCL can be seen in 7% to 53% of children with JIA, anti-β ₂ GPI and LA, antibodies that are thought to carry higher risk for thrombosis than aCL, were found in fewer than 5% of patients.

Isolated cases of APS were reported in a variety of other pediatric autoimmune diseases, particularly in systemic vasculitis, where vasoocclusive events with APLA have been reported in IgA vasculitis (Henoch–Schönlein purpura), ^, Behçet disease, and polyarteritis nodosa. In addition, APLA with thrombotic disease are seen in immune thrombocytopenic purpura, ^, hemolytic-uremic syndrome, ^, and rheumatic fever. Patients with immune thrombocytopenic purpura and APLA may have both bleeding and thrombotic complications.

Infections

Many viral and bacterial infections in childhood can induce de novo production of APLA in previously antibody-negative patients. Infection-induced APLA tend to be transient, present in low titer, and generally not associated with APS clinical manifestations. The majority of postinfectious APLA differ immunochemically from those seen in patients with autoimmune diseases and do not require the presence of cofactor plasma proteins such as β ₂ GPI for binding. An association of APLA with infection is further supported by seasonal occurrences of APLA.

The distinction between nonpathogenic postinfectious APLA and thrombogenic autoimmune APLA is not absolute. Several infections are known to induce heterogeneous APLA, including pathogenic antibodies against β ₂ GPI and prothrombin, resembling those seen in autoimmune diseases. ^, ^, Preceding or concomitant infection occurred in 10% of children with primary APS or APS associated with autoimmune disease and in up to 60% in children with CAPS. Pediatric APS was most often associated with varicella-zoster virus, parvovirus B19, human immunodeficiency virus (HIV), streptococcal and staphylococcal infections, gram-negative bacteria, and Mycoplasma pneumonia . The mechanism for infectious induction of APS may be molecular mimicry between antigens on infectious agents and β ₂ GPI or unmasking of cryptic antigenic determinants of naturally occurring anti-β ₂ GPI, thus initiating the prothrombotic effects of APLA described in the section on “Etiology and Pathogenesis.” ^,

Malignancies

There have been isolated case reports of the association of APLA with thrombotic events in children with various malignancies, including solid tumors and lymphoproliferative and hematological malignancies. Malignancy is an important risk factor for childhood thrombosis, and the presence of APLA may enhance the thrombophilic risk of children with neoplasms. ^, However, APLA are identified as an acquired thrombotic risk factor in fewer than 3% of these malignancy-associated childhood thromboses. Published data suggest that APS associated with malignancies accounts for fewer than 1% of all children with APS. It appears that APLA-related thrombotic events associated with malignancies are more common in the elderly than in children, particularly in association with solid tumors. ^, ^,

Healthy Children

Low levels of APLA are found in up to 25% of apparently healthy children, which is higher than the rate seen in healthy adults. Such naturally occurring APLA are usually transient and present in low titer, and they can be the result of previous infections or vaccinations. ^, ^, ^, In apparently healthy children, the estimated frequency of aCL ranges from 3% to 28%, and the estimated frequency of anti-β ₂ GPI ranges from 3% to 7%. ^, LA have been described in otherwise healthy children, usually as a prolonged activated partial thromboplastin time (aPTT) on preoperative coagulation screening. ^, The risk of future thrombosis is very low in otherwise healthy children who were incidentally found to have positive APLA.

Increasing evidence suggests that the developing immune system can respond to nutritional antigens by forming nonpathogenic anti-β ₂ GPI during early childhood. ^, ^, Bovine β ₂ GPI from ingested milk or beef may act as an oral immunization agent to induce transient production of IgG anti-β ₂ GPI in up to 55% of healthy infants. Infant intestinal mucosa is more permeable to large molecules than that of older children and adults. ^, During prospective follow-up of infants born to mothers with APS or APLA-positive autoimmune disease, aCL titers progressively decline by 6 to 12 months of age; all infants are negative for aCL. ^, In contrast, anti-β ₂ GPI is found at 12 months of age in up to 64% of infants born to APLA-positive mothers and in 33% of infants born to mothers with APLA-negative autoimmune disease, further implying postnatal de novo synthesis of anti-β ₂ GPI. Current evidence suggests that postnatally produced anti-β ₂ GPI in infants confers low thrombosis risk, perhaps because of specificity for domain V of β ₂ GPI, different from pathogenic anti-β ₂ GPI found in APS, which preferentially target domain I. ^, ^, Given the possibility of detecting dietary-induced anti-β ₂ GPI in infants, it seems reasonable to track aCL, but not anti-β ₂ GPI, to evaluate the disappearance of passively acquired maternal APLA.

Etiology and Pathogenesis

Discerning differences between benign APLA that are detectable in healthy children from those associated with clinical APS is a goal of research in the field. APS can be familial or hereditary, suggesting that genetic clues exist to the pathogenesis of APS. If there is a second prothrombotic risk factor, such as underlying autoimmune disease or heterozygous deficiency of a natural anticoagulant, the risk of thromboembolic disease of APLA rises dramatically. This observation generated the “two hit theory,” implying that although APLA may inhibit repair of endothelial and platelet surface defects, thereby promoting thrombosis, a perturbation of these membranes in some way is required for pathological thrombosis to occur. Despite progress, it is still difficult to predict in which autoantibodies, and in what setting, APLA will cause thromboembolic disease in any individual child.

Pathophysiology

APLA cause disease through myriad effects on endothelial cells, platelets, monocytes, and neutrophils (summarized in Box 24.2 ). These antibodies promote complement activation, ^, inhibit physiological anticoagulants (activated protein C, antithrombin III, and the annexin A5 anticoagulant shield), and impair fibrinolysis through activation of thrombin activatable fibrinolysis inhibitor (TAFI). Furthermore, APLA increase the procoagulant state of platelets, endothelial cells, and leukocytes. Endothelial oxidative stress, mediated by APLA-induced decrease in paraoxonase activity and effects on endothelial nitric oxide synthase, increase lipid peroxidation in plasma and direct antibody-mediated cross-linking and activation of the platelet apolipoprotein E receptor 2.

Box 24.2

Mechanisms of Action of Antiphospholipid Antibodies

vWF, von Willebrand factor.

Platelet Activation

Aggregation
Thromboxane release

Monocyte Activation

Inflammatory cytokine production
Increased monocyte tissue factor expression

Endothelial Activation

Tissue factor expression and secretion
Increased vWF expression
Expression of adhesion molecules

Impaired Function of Activated Protein C

Decreased Binding of C4 to C4BP

Increased C4BP binding of protein S

Promote Clot Formation

Impair Thrombolysis

Other broad-ranging biological effects of APLA not only disturb the interaction between cells and plasma but also disrupt the orderly function of biological membranes. There is growing evidence that APLA promote atherosclerosis and cardiac valve disease (Libman–Sacks endocarditis), and they can directly contribute to both trophoblast ^, and neuronal dysfunction.

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