eMedicine Specialties > Pediatrics: General Medicine > Rheumatology
Antiphospholipid Antibody Syndrome
Updated: Aug 4, 2009
Introduction
Background
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).1,2,3,4,5,6,7,8,9,10,11
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.
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.12
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.13
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.14,15,16
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.17
Updated clinical criteria
- 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
- 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.18
- 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.
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
- Immunoglobulin A (IgA) aCL
- IgA anti-b2GPI
- Antiphosphatidylserine antibodies
- Antiphosphatidylethanolamine antibodies
- Antibodies against prothrombin alone
- Antibodies to the phosphatidylserine-prothrombin complex
Pathophysiology
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.19,20,21,22,23,24,1,25,26,27,28,29,30,31,32,33- 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).
Frequency
United States
- 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
- 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.
Mortality/Morbidity
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.)
Race
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.
Sex
- 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.
Age
- Antiphospholipid antibody syndrome has been described in patients of all ages. The prenatal, perinatal, and neonatal periods can be affected.
Clinical
History
Vasospastic or vaso-occlusive events can occur in any organ system in patients with antiphospholipid antibody (aPL) syndrome (APS); thus, a thorough history should be taken, and an organ-specific review of systems should be performed. A broad spectrum of involvement ranging from rapidly progressive to clinically silent and indolent may be present.2,3,4,5,6,11
- Head, ears, eyes, nose, and throat
- Blurred or double vision
- Visual disturbance ("wavy lines,” “flashing lights")
- Visual loss (field cuts, total vision loss)
- Cardiorespiratory
- Chest pain
- Radiating arm pain
- Shortness of breath
- Gastrointestinal
- Abdominal pain
- Abdominal distension (bloating)
- "Abdominal migraine"
- Emesis
- Peripheral vascular
- Leg pain
- Leg swelling
- Claudication
- Digital ulcerations
- Leg ulcerations
- Cold-induced finger pain, toe pain, or both
- Musculoskeletal
- Bone pain
- Joint pain
- Cutaneous
- Purpuric rashes, petechial rashes, or both
- Persistent or transient lacy rashes of livedo reticularis
- Dusky fingers, dusky toes, or both
- Blanching of fingers, blanching of toes, or both
- Neurologic and psychiatric
- Syncope
- Seizures
- Headache (migraine)
- Paresthesias
- Paralysis
- Ascending weakness
- Tremors
- Abnormal movements
- Memory loss
- Problems with concentrating, reading comprehension, calculations (change in school performance)
- Endocrine - Weakness, fatigue, arthralgia, abdominal pain (Addisonian features)
- Genitourinary/renal
- Hematuria
- Peripheral edema
- Pregnancy-related history - Not expected to be of frequent concern in the field of pediatrics but may be significant in teenagers
- Family history
- A strong family history is more pertinent to most pediatric patients and may assist in identifying patients at risk.
- Family history may include the following:
- Frequent miscarriage, premature birth, intrauterine growth retardation (IUGR), oligohydramnios, chorea gravidarum, placental infarction, preeclampsia, toxemia of pregnancy, or neonatal thromboembolism
- Myocardial infarction or stroke in persons younger than 50 years
- Deep vein thrombosis (DVT), phlebitis, or pulmonary embolus
- Strong family history of migraine, Raynaud phenomenon, or transient ischemic attacks (TIAs)
- Medication history - Use of oral contraceptives at the time of a clinical event
Physical
Physical findings are specific to the affected organ and can involve any organ system.34 Catastrophic antiphospholipid antibody syndrome (CAPS) is a multisystem failure secondary to thrombosis, infarction, or both and has a picture of microangiopathy on histology.35,36,37,38,18,39
- Peripheral vascular
- Point tenderness to palpation of bone or joints (bone infarction): See Media file 18.
CAPS, Bone Infarction - MRI (High Resolution Proton Density and STIR images) and Nuclear Bone Scan - Patient (same as in images 16, 17, 19) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. MRI shows multiple infarctions in the distal tibia, tarsal bones and metatarsal bones (extensive bone marrow edema and increased T1 with fat saturation signal in the calcaneus bones). Flow and early blood pool images of technetium 99m bone scan show increase in activity in both heel regions with focal areas of decreased activity in the center of each calcaneus.
- Pain on range of motion of joints without arthritis (avascular necrosis)
- Limb swelling (DVT)
- Peripheral edema (DVT, renal vein thrombosis)
- Decreased capillary refill (arterial thrombosis, vasospasm)
- Decreased pulses (arterial thrombosis, vasospasm)
- Decreased perfusion (arterial thrombosis, vasospasm)
- Gangrene (arterial thrombosis, infarction): See Media files 16-17.
A patient (the same as in media files 17-19) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. Extensive involvement of all digits is noted, some with distal infarction and dry gangrene, others healing with residual eschar (and undermining epithelialization), and some with re-epithelialization and scarring. Healed superficial epidermal damage and desquamation is also present.
A patient (the same as in Media files 16, 18, and 19) with multisystem small vessel coagulopathy (microangiopathy) but no known underlying disease process. Eschar is still present on first digit bilaterally. More superficial lesions are shown here than are shown in Media file 16, with evolution and healing of lesions on all other toes.
- Point tenderness to palpation of bone or joints (bone infarction): See Media file 18.
- Pulmonary - Respiratory distress, tachypnea (pulmonary embolism [PE], pulmonary hypertension)40
- Renal41,42,43,44,45,46
- Hypertension (renal artery thrombosis, intrarenal vascular lesions)
- Hematuria (renal vein thrombosis)
- Acute renal insufficiency (intrarenal vascular lesions): See Media files 10-12.
Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Top: Thrombosed kidney vessels (periodic acid-Schiff [PAS], original magnification X40). Bottom: Thrombosed kidney vessels (PAS, original magnification X20). Lumen is filled with eosinophilic fibrin with overlying injured endothelial cells. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.
Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Top: Thrombosed kidney vessel (hematoxylin and eosin [H&E] stain, original magnification X20). Lumen is occluded with fibrin. A perivascular stromal reaction with degenerating inflammatory cells is observed. Bottom: Thrombosed kidney vessel (H&E stain, original magnification X20). Lumen is occluded with fibrin. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.
Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE), World Health Organization (WHO) class IV lupus nephritis, and acute renal failure. Thrombosed kidney vessel with recanalization (arrows) (Jones stain, original magnification X20). Architectural distortion in the surrounding stroma is observed. The authors acknowledge the help of Karen W. Eldin, MD, in preparing this image.
- Cardiac47,48,49,50,51,52
- Insufficiency murmur of aortic, mitral valve (endocarditis)
- Chest pain, diaphoresis (myocardial infarction)
- GI
- Right upper quadrant tenderness, hepatomegaly (Budd-Chiari syndrome, hepatic small vessel thrombosis, hepatic infarction)
- Abdominal tenderness (mesenteric artery thrombosis)
- Endocrine - Muscle weakness, progressive stiffening of pelvic and thigh muscles with flexion contractures associated with adrenal insufficiency (adrenal infarction/hemorrhage)53
- Ocular
- Retinal artery occlusion
- Retinal vein thrombosis
- Skin manifestations
- Livedo reticularis: See Media files 1-2.
Palmar livedo reticularis associated with antiphospholipid antibody syndrome may range from a lacy, flat, reticulated pattern to a more confluent, nonblanching, slightly raised rash (secondary to extravasation of RBCs and plasma).
Livedo reticularis of the upper and lower extremities in a 15-year-old adolescent with primary antiphospholipid antibody syndrome. The pattern is lacy, flat, and nonblanching. The purplish hue is from stasis in the small vessel beds.
- Purpuric lesions: See Media file 14.
Livedo reticularis of the upper extremities, which developed as petechiae in the classic lacy, reticular pattern and evolved as a confluent, nonblanching, slightly raised purpuric rash in the same reticular pattern. Same patient as in Media file 13.
- Superficial thrombophlebitis
- Vasospasm (ie, Raynaud phenomenon): See Media file 3.
Muddy discoloration and mild diffuse swelling of the fingers observed as part of the Raynaud phenomenon, which is associated with antiphospholipid antibody syndrome. At room temperature, this patient still has decreased capillary refill and cold fingers despite treatment with pentoxifylline. The discoloration extends proximally onto the palms and turns blue-purple when exposed to cold.
- Splinter hemorrhages (periungual, subungual): See Media file 4.
Linear splinter hemorrhages are found under the nails of fingers and toes. These may be solitary or multiple and appear intermittently.
- Peripheral infarctions (digital pitting): See Media file 15.
Digital infarctions in a patient with systemic lupus erythematosus with antiphospholipid syndrome (APS) and long-standing Raynaud symptoms. Multiple and repeated digital infarctions are depicted, resulting in ulcerations and scarring. Scars and hyperpigmentation are also seen on the palmer aspect of hands and fingers.
- Skin ulcerations (eg, leg ulcers)
- Petechiae (associated with thrombocytopenia): See Media files 13-14.
Antiphospholipid antibody syndrome in a patient with positive test results for antiphospholipid antibody and lupus anticoagulant who has systemic lupus erythematosus (SLE) and thrombocytopenia. Livedo reticularis of the upper extremities, which developed as petechiae in the classic lacy, reticular pattern, is observed.
Livedo reticularis of the upper extremities, which developed as petechiae in the classic lacy, reticular pattern and evolved as a confluent, nonblanching, slightly raised purpuric rash in the same reticular pattern. Same patient as in Media file 13.
- Bruising (associated with thrombocytopenia)
- Livedo reticularis: See Media files 1-2.
- Central or peripheral nervous system abnormalities54,55,56,57
- Stroke, cerebrovascular accident (CVA)
- TIA
- Paresthesia, polyneuritis, or mononeuritis multiplex (vasovasorum ischemia/infarction)
- Paralysis, hyperreflexia, weakness (transverse myelitis, Guillain-Barré syndrome)
- Movement disorders - Choreiform tremors (cerebral, cerebellar, basal ganglia infarction)
- Multiple sclerosis–like disorder
- Learning disability
- Short-term memory loss
Causes
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], 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
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Further Reading
Keywords
anti-phospholipid antibody syndrome, Hughes syndrome, Hughes' syndrome, antiphospholipid syndrome, anti-phospholipid syndrome, APS, APLS, Sneddon syndrome, Sneddon's syndrome, thrombosis, primary antiphospholipid syndrome, PAPS, secondary antiphospholipid syndrome, antiphospholipid, aPl, deep venous thrombosis, arterial occlusive events, migraine headache, Raynaud phenomenon, transient ischemic attack, TIA, systemic lupus erythematosus, SLE, lupus anticoagulant, LAC, migraine headache, peripheral vasospasm, thrombocytopenia, anticardiolipin antibody, aCL antibody, cerebrovascular accident, myocardial infarction, endocarditis, pulmonary emboli, treatment, diagnosis
