Pediatric Antiphospholipid Antibody Syndrome

Antiphospholipid (aPL) antibodies have been found in association with clinical symptoms such as deep venous thrombosis, arterial occlusive events (eg, stroke, myocardial infarction), and recurrent fetal loss. They are also associated with vasospastic phenomena such as migraine headache, Raynaud phenomenon, and transient ischemic attack (TIA). ^{[3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]}

The terminology associated with antiphospholipid antibodies has been fraught with misnomers. Conley and Hartmann observed a prolongation in the prothrombin time (PT) in a series of patients with systemic lupus erythematosus (SLE), which was later termed the lupus anticoagulant (LAC). This term is misleading for the following reasons:

• The LAC phenomenon can be caused by any number of antibodies to the phospholipid template of the coagulation cascade.

• These antibodies are frequently found outside the clinical spectrum of SLE.

• Although these antibodies are responsible for a prolongation of the activated partial thromboplastin time (aPTT) in vitro, they are associated with a hypercoagulable state in vivo.

In the early 1980s, Harris identified anticardiolipin antibodies in a subset of these patients. Since that time, antibodies to phospholipids alone have been determined to be associated with infectious causes more often. In contrast, antibodies to combinations of phospholipids and serum proteins (eg, β 2-glycoprotein I [β 2-GPI] or prothrombin) are more likely associated with the vasculopathic events of antiphospholipid antibody syndrome (APS).

Antiphospholipid antibodies associated with vaso-occlusive events without any underlying disease process is termed the primary antiphospholipid antibody syndrome (PAPS). The presence of antiphospholipid antibodies and a vaso-occlusive event superimposed on an underlying disease, such as SLE or malignancy, is a secondary antiphospholipid antibody syndrome. ^[14]

Preliminary classification criteria for "definite" antiphospholipid antibody syndrome were proposed in a report from the Eighth International Symposium on Antiphospholipid Antibodies and were published in Arthritis and Rheumatism. ^[15]

The purpose of the report was to define the essential features of antiphospholipid antibody syndrome in order to facilitate studies of treatment and causation. This definition was intended to encompass the clinical and laboratory features most closely associated with antiphospholipid antibodies in prospective studies based on the strongest experimental evidence. The hope was to use the "cleanest" patient populations for basic research and clinical treatment studies. These criteria were not meant to supplant the physician's clinical judgment in making the diagnosis in any particular patient. Although features such as migraine headache, peripheral vasospasm, and thrombocytopenia were excluded from the published criteria, they were argued to be valid and useful clinical parameters in arriving at the diagnosis of antiphospholipid antibody syndrome in the clinical setting at the Ninth International Symposium on Antiphospholipid Antibodies. ^{[16, 17, 18]}

In a consensus conference held at the 11th International Symposium on Antiphospholipid Antibodies, existing evidence on clinical and laboratory features of antiphospholipid antibody syndrome was appraised and amendments to the Sapporo criteria were proposed. The criteria were reiterated to be used for clinical research to define homogenous populations for studies. Therefore, in order to address the needs of clinicians and to expand the data for future research, the discussion included definitions on features of antiphospholipid antibody syndrome that were not included in the updated criteria for use clinically and in research. These were published as the "International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Antibody Syndrome (APS)" in J Thrombosis Haemost. ^[19]

Updated clinical criteria

Clinical criteria include the following:

• Vascular thrombosis - One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ confirmed by imaging studies, Doppler studies, or histopathology (without significant vessel wall inflammation)

• Pregnancy morbidity (normal morphology on ultrasonography or direct examination findings)

  • One or more unexplained fetal deaths at more than 10 weeks’ gestation

  • One or more premature births at less than 34 weeks’ gestation due to severe preeclampsia, eclampsia, or placental insufficiency

  • Three or more unexplained consecutive spontaneous abortions at less than 10 weeks’ gestation, excluding maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes

In research studies of patient populations that contain more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify subjects according to the 3 groups above.

Updated laboratory criteria

Laboratory criteria include the following:

• Anticardiolipin (aCL) antibody of the immunoglobulin G (IgG)/immunoglobulin M (IgM) isotype in medium/high titer (>40 IgG phospholipid units [GPL], >40 IgM phospholipid units [MPL], or >99th percentile) on 2 or more occasions at least 12 weeks apart (measured by a b2-GPI–dependent enzyme-linked immunosorbent assay [ELISA]).

• Lupus anticoagulant on 2 or more occasions at least 12 weeks apart, according to the guidelines set forth by the International Society of Thrombosis and Hemostasis Scientific Subcommittee on Lupus Anticoagulants/Phospholipid-dependent Antibodies. ^[20]

  • Prolonged phospholipid-dependent coagulation (eg, aPTT, Kaolin clotting time [KCT], dilute Russell viper venom test, dilute PT)

  • Failure to correct the prolonged coagulation time by a mix with platelet poor plasma (PPP)

  • Shortening or correction of the prolonged coagulation time with excess phospholipid

  • Exclusion of other coagulopathies (eg, factor VIII inhibitor, heparin)

Investigators are strongly advised to classify patients (in research studies) with antiphospholipid antibody syndrome into one of the following categories:

• I - Patients with more than 1 laboratory criteria (any combination)

• IIa - Patients with LAC present alone

• IIb - Patients with aCL antibody present alone

• IIc - Patients with anti-β 2-glycoprotein-I antibody present alone

A patient must meet at least one clinical and one laboratory criterion for a diagnosis of antiphospholipid antibody syndrome. Classification of antiphospholipid antibody syndrome should be avoided if less than 12 weeks or more than 5 years separate a positive antiphospholipid antibody test and the clinical manifestation. ^[21]

Patients with antiphospholipid antibody syndrome participating in research studies should be further subgrouped according to the presence or absence of additional risk factors for thrombosis. Patients should not be excluded from APS trials because of coexistent inherited or acquired factors for thrombosis.

Patients with antiphospholipid antibody syndrome participating in research studies who fulfill the revised classification criteria should be classified separately from patients with “features associated with antiphospholipid antibody syndrome” or with “noncriteria features of antiphospholipid antibody syndrome.” These features, which were discussed by the consensus panel but not included in the revised criteria, include the following:

• Heart valve disease

• Livedo reticularis

• Thrombocytopenia

• Nephropathy

• Neurological manifestations ^[22]

• Immunoglobulin A (IgA) aCL

• IgA anti-b2GPI

• Antiphosphatidylserine antibodies

• Antiphosphatidylethanolamine antibodies

• Antibodies against prothrombin alone

• Antibodies to the phosphatidylserine-prothrombin complex

The mechanism or mechanisms by which the antiphospholipid antibodies interact with the coagulation cascade to produce clinical events are largely speculative and have not been clearly elucidated. The presence of preexisting or coincident vascular (endothelial) damage along with the identification of an antiphospholipid antibody as requisites for the emergence of a thrombotic complication has been coined the "2-hit" hypothesis. ^{[23, 24, 25, 26, 27, 28, 3, 29, 30, 31, 32, 33, 34, 35, 36, 37]}

• Possible mechanisms by which antiphospholipid antibodies may induce thrombotic events include the following:

  • Antiphospholipid antibodies may combine with platelet membrane phospholipids, resulting in increased platelet adhesion and aggregation.

  • Antiphospholipid antibodies may combine with the endothelial cell membrane phospholipids along with b2-GPI and induce endothelial cell damage, impaired prostacyclin production, increased platelet adhesion, and aggregation.

  • Endothelial cell damage may also result in decreased production of endothelium-derived relaxing factor and, thus, increased vasospasm and ischemia.

  • Antiphospholipid antibodies can stimulate tissue factor expression by endothelial cells, monocytes, and neutrophils with induction of cellular activation and respiratory burst leading to membrane damage.

  • In secondary antiphospholipid antibody syndrome, vascular endothelial cell damage has already occurred, enhancing the vascular spasm/occlusion, ischemia/infarction, and reperfusion injury.

  • b2-GPI may be bound up by antiphospholipid antibodies and (1) prevented from covering up exposed procoagulant inner membrane leaflet phospholipids or (2) blocked from inhibiting platelet prothrombinase activity.

  • b2-GPI and oxidized low-density lipoprotein (oxLDL) complexes may be bound up by antiphospholipid antibodies, cleared by macrophages, and, thus, promote accelerated development of atherosclerosis in autoimmune patients.

  • Antiphospholipid antibodies may interfere with the interaction of coagulation protein C and coagulation protein S and, thus, affect the formation of the APC coagulation control complex (activated protein C, protein S, and factor V).

• Possible mechanisms by which antiphospholipid antibody might be generated include the following:

  • Autoimmunity may be a factor; a break in tolerance may lead to an "escaped clone."

  • Closely related to the previously mentioned mechanism is the concept that antiphospholipid antibodies are a response to inner membrane leaflet antigens (ie, phosphoserine) that are exposed in apoptotic blebs on cells not eliminated from the circulation because of an overloaded or defective clearance system.

  • Antiphospholipid antibodies may also be cross-reactive antibodies induced by exogenous antigens from infectious organisms (eg, viral or bacterial).

Canaud et al studied the molecular pathways involved in the vasculopathy of the antiphospholipid syndrome. The researchers used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. The mTORC pathway is involved in the vascular lesions that occur in patients with antiphospholipid syndrome. According to this study the mTOR inhibitor sirolimus may help prevent vasculopathy in patients with the disease. ^{[38, 39]}

The causes of antiphospholipid antibody syndrome are unknown (see Pathophysiology).

The association of thrombotic events with preexisting or coincident vascular perturbation is emphasized by the high incidence of antiphospholipid antibody syndrome in patients with the following conditions:

• Vascular inflammation, vasculitis

  • Autoimmune disease (eg, systemic lupus erythematosus [SLE] ^[40] , cryoglobulinemia)

  • Infectious processes (eg, hepatitis, parvovirus, syphilis)

• Malignancy (eg, carcinoma, leukemia)

• Vascular trauma

  • Postsurgery (eg, cardiac)

  • Trauma (eg, accidental)

• Drug-induced state (eg, procainamide, phenytoin, hydralazine, chlorpromazine)

• Hemodialysis-associated condition (increased antiphospholipid antibody antibodies over time on dialysis)

  • Cuprophane membrane exposure

  • Oxidative stress

United States statistics

Antiphospholipid antibodies are reportedly present in 1-15% of the general population (higher in elderly persons). These antibodies are reportedly present in as many as 70% of patients with SLE; however, the frequency rate of antiphospholipid antibody syndrome (ie, antiphospholipid antibodies plus a clinical event) is far lower.

In patients with SLE, a history of thrombosis was reported in 61% of those with positive test results for LAC, in 52% of those who had positive anticardiolipin antibodies, and 24% of those who had no antiphospholipid antibodies.

International statistics

No major differences have been noted between frequency rates in the United States and frequency rates worldwide. A large multicenter European SLE registry suggests that 3-7% of patients with SLE and antiphospholipid antibodies are at risk for new-onset thrombosis.

Race-, sex-, and age-related demographics

Overall, no specific race predilection has been observed.

The frequency rate of primary antiphospholipid antibody syndrome is skewed by race predilection of risk factors for thrombosis and atherosclerotic disease. The frequency of secondary antiphospholipid antibody syndrome is skewed by race predilection for autoimmune diseases.

In secondary antiphospholipid antibody syndrome, the frequency rate is skewed by the female predominance in autoimmune diseases (eg, SLE) in general. In primary antiphospholipid antibody syndrome, the frequency rate is skewed by the inclusion of pregnancy-related events in the classification schema.

In both antiphospholipid antibody syndrome and primary antiphospholipid antibody syndrome, the frequency rate related to sex is equalized in young patients, especially prior to the onset of puberty.

Antiphospholipid antibody syndrome has been described in patients of all ages. The prenatal, perinatal, and neonatal periods can be affected. The onset of disease has been reported in children as young as 8 months. ^[13]

The long-term prognosis varies and depends on the tissue damage incurred and the organ system or systems affected. Clinical manifestations that are associated with a worse prognosis include the following ^{[41, 42, 43]} :

• Pulmonary hypertension

• Neurologic involvement (eg, CNS involvement, transverse myelopathy)

• Myocardial ischemia

• Nephropathy

• Gangrene of the extremities

• Catastrophic antiphospholipid antibody syndrome

Morbidity/mortality

Mortality and morbidity are related to clinical manifestations. An increased incidence of the following is seen in young individuals:

• Cerebrovascular accident (CVA), stroke
• Myocardial infarction
• Endocarditis (may lead to valvular replacement)
• Pulmonary emboli (may lead to pulmonary hypertension)
• Deep vein thrombosis (DVT)
• Fetal loss from second trimester to the perinatal period, including intrauterine growth retardation (IUGR), prematurity, and symptoms of toxemia
• Catastrophic antiphospholipid antibody syndrome (multisystem failure secondary to thrombosis, infarction, or both may lead to death in 50% of cases)

Complications

Hemorrhage may occur as a result of overaggressive therapy.

Rethrombosis may occur as a result of inadequate therapy.

Catastrophic antiphospholipid antibody syndrome can lead to death (50% mortality rate).

Lifestyle counseling is indicated to educate patients and their families about the risk factors that are known to complicate the prognosis of patients with antiphospholipid antibody syndrome.

Dietary manipulation is recommended to prevent obesity, hyperlipidemia, and hypertension, starting at a young age, especially in patients with a family history of these problems.

Dietary manipulation is recommended to decrease consumption of methionine-containing foods that might increase homocysteine levels in patients carrying mutations of the gene that encodes for methylene tetrahydrofolate reductase mutation (MTHFR). Folate deficiencies need to be identified and corrected in these patients to control homocysteine levels.

Counsel adolescents about the potential risks of smoking tobacco in this setting. Provide smoking cessation programs for patients who already have started smoking.

In patients with a secondary antiphospholipid antibody syndrome, encourage compliance with medications for control of underlying disease processes, such as vasculitis and systemic lupus erythematosus (SLE).

Dietary counseling is indicated for patients on oral anticoagulants, such as the following recommendations:

• Maintenance of a consistent diet of foods containing vitamin K

• Avoidance of foods and herbs with anticoagulant properties

Counsel patients regarding the risks of oral contraceptive use and the need for alternative methods of contraception.

Current information for patients and their families can be obtained from the excellent Web sites from the St. Thomas Hospital in London (Hughes Syndrome, Hughes Syndrome Foundation).

For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education articles Blood Clot in the Legs and Stroke.