Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, manifesting with vascular thrombosis and/or recurrent fetal loss.1 It is a complex illness that paradoxically causes either too much coagulation or too little, although thrombosis is most commonly seen.
Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies directed against phospholipids, a group of molecules that make up most cell membranes. Phospholipids are bound to, and circulate with, positively charged phospholipid-binding proteins. Cell membranes are involved in many biological functions, including coagulation. Several key reactions involved in blood clotting require membranes that contain certain negatively charged phospholipids.
Primary APS occurs in patients without clinical evidence of another autoimmune disease, whereas secondary APS occurs in association with connective tissue disorders, most commonly systemic lupus erythematosus (SLE), or another rheumatic or autoimmune disorder. About 50% of patients have the primary form of the disease.2 Primary APS occurs more commonly in young- to middle-aged adults; however, it also manifests in children and elderly people. Disease onset has been reported in children as young as 8 months. A female predominance is documented, particularly for secondary APS. Secondary APS is present in 10% to 15% of patients with SLE.3,4
Antiphospholipid Antibodies Associated with APS
The aPL are a heterogeneous group of autoantibodies that may be present in healthy persons. Prevalence varies between 0% and 9% depending on the aPL, but positive findings seldom persist.2 These antibodies rise transiently in acute settings and are especially prevalent in thrombosis. The antigenic targets of aPL are uncertain. Although the name implies that phospholipids such as cardiolipin are the targets, the major antigens are most likely phospholipid-binding proteins, or protein cofactors, bound to phospholipids. The most important protein cofactor in APS is ?2 -glycoprotein I (?2GPI; also called apolipoprotein H). ?2 GPI appears to be an in vivo anticoagulant, interfering with the contact activation of the intrinsic pathway in the coagulation cascade.1 ? 2GPI is bound to cardiolipin (CL) and lupus anticoagulant (LA), among other phospholipids. Other phospholipid-binding proteins include prothrombin, protein C, protein S, factor VIII, and annexin V. Many of these protein cofactors play a role in regulating coagulation. Binding by aPL interferes with normal function and may lead to a procoagulant state.
The aPL may also be present in patients with infections such as syphilis, infectious mononucleosis, AIDS, and exposure to certain medications (e.g., chlorpromazine). These aPL are not believed to have clinical sequelae because they bind directly to phospholipids rather than to phospholipid-binding proteins. The aPL can be detected by enzyme-linked immunosorbent assay (ELISA), using plastic wells coated with negatively charged phospholipids. ELISA, however, may fail to distinguish aPL that bind to phospholipids as opposed to phospholipid-binding proteins (FIGURE 1).1
The most important subgroups of aPL
associated with APS are LA, anticardiolipin antibodies (aCL), and anti-?2
GPI antibodies. Detection of these aPL are complicated by poor standardization
LA is an antibody specific to either phospholipid-bound prothrombin or ?2 GPI.5 In patients with SLE, LA correlates particularly well with thrombosis. LA blocks phospholipid surfaces integral to coagulation.2 By inhibiting the conversion of prothrombin to thrombin, LA interferes with clot formation. This interference is measurable by coagulation assay, activated partial thromboplastin time (aPTT), presenting as prolonged clotting time.6 In order to confirm the presence of LA, international consensus criteria recommend performing at least two different types of assay for LA, with concurring results. The most common LA tests are aPTT and the dilute Russell viper venom time (dRVVT). The dRVVT is performed by adding Russell viper venom to serum. Normally, the venom activates the coagulation cascade and coagulation occurs. A positive result occurs when: 1) coagulation is prolonged instead; 2) adding normal serum fails to correct this; but 3) normal coagulation is resumed by the addition of phospholipids (FIGURE 2 ).7 Anticoagulant therapy interferes with the detection of LA, and testing should be postponed if treatment is under way.8
The aCL bind to cardiolipin, a phospholipid, through ?2GPI, and are detected by ELISA.5 Notably, aCL that occur with syphilis bind directly to cardiolipin in the absence of ?2GPI. This binding is inhibited by human ?2GPI and its antibody (FIGURE 1) and highlights the difference between aCL associated with thrombosis and aCL associated with infection. The immunoglobulin isotypes associated with aCL are IgG, IgM, and IgA. It is believed that the IgG isotype is most strongly associated with thrombosis.2 Current criteria for the classification of APS recommend the use of ELISA to measure ?2 GPI-dependent anticardiolipin IgG and IgM antibodies (TABLE 1).7
Anti-?2GPI antibodies were added to the modified Sapporo criteria for APS diagnosis. As noted earlier, ?2GPI bound to negatively charged phospholipids is the major target for aPL. Anti-?2GPI antibodies are an independent risk factor for thrombosis and obstetric complications.6,9 Current criteria for classifying APS also recommend ELISA to measure anti-?2GPI IgG and IgM antibodies ( TABLE 1).
The presence of aPL alone does not
necessarily have clinical implications, but in some people, aPL may trigger
thrombosis. One mechanism for aPL-associated thrombosis involves binding of ?
2GPI by autoantibodies, which in turn facilitates binding to membrane
phospholipids and/or phospholipid-associated receptors. The resulting anti-?
2GPI/?2GPI complex activates platelets, monocytes, and
endothelial cells through binding of ?2GPI with specific cell
surface receptors (FIGURE 3), leading to a procoagulant state. Other
proteins that are important in regulating coagulation (i.e., prothrombin,
protein C, protein S, and annexin V), may also be targeted by aPL.6
Another mechanism involves the binding of aPL to endothelial cells, which
induces activation and promotes expression of cytokines and metabolism of
prostacyclins.6 Activation of endothelial cells promotes
coagulation.10 There is also evidence that aPL promote the
activation and aggregation of platelets. Finally, thrombosis in APS has been
linked to heparin-induced thrombocytopenia.6 In APS, there is a
high rate of recurrence of similar thrombotic events. A "second hit"--such as
an infection leading to cytokine production or traumatic injury to the
vascular bed leading to endothelial activation--and nonimmunologic
procoagulant factors are necessary for thrombosis to occur.1
An international consensus statement on the preliminary classification criteria for APS was published in 1999, called the Sapporo criteria.11 These criteria were updated in 2006.7 A diagnosis of APS is made when a person presents with at least one of the clinical and at least oneÜ of the laboratory criteria. Specifically, these are: 1) the occurrence of clinical manifestations, such as vascular thrombosis or obstetric complication; and 2) the persistent presence of aPL. The aPL specified in the consensus criteria are LA, aCL (medium-to-high titer IgG and/or IgM isotype), and ?2GPI antibodies (high titer IgG and/or IgM isotype). To demonstrate that the results are persistent, positive laboratory results must be confirmed on two or more occasions, at least 12 weeks apart. The qualifying clinical criteria and quantitative laboratory findings are summarized in TABLE 1.7
Management of APS
Prophylaxis in aPL-positive Patients: Given that laboratory criteria for APS are not routinely performed, APS is usually identified during the differential diagnosis of one of the clinical criteria. Hence, treatment is generally considered in aPL-positive patients after a thrombotic event occurs. If aPL are identified in asymptomatic patients, any factor predisposing for thrombosis (e.g., defects in coagulation factors, platelet defects, hyperviscosity, oral contraceptives, estrogen replacement therapy, nephrotic syndrome, smoking, or surgery) should be corrected, if possible.
The role of aspirin for primary prophylaxis against a thrombotic event is controversial. One report found that aspirin (325 mg/day) in women who are aPL positive and with a history of fetal loss may protect against thrombosis. 12 On the contrary, a case-control study within the Physicians
Health Study found that aspirin (325
mg/day) did not protect against venous thromboembol
ism in males with aCL.13 Currently, there are insufficient data to
recommend antithrombotic prophylaxis in patients who are aPL positive without
a history of thrombosis. In women who are aPL positive and with a history of
fetal loss, however, prophylaxis with aspirin may be considered.
Clinical Manifestations and Management
Vascular Thrombosis: The defined clinical criteria are arterial, venous, or small vessel thrombosis, excluding superficial thrombi.7 Venous thromboembolism is the most common initial clinical manifestation among patients with APS, occurring in 32% who meet Sapporo criteria.2 The most common form is deep venous thrombosis of the lower extremities. Up to half of those patients have pulmonary emboli.6 Arterial thromboses are most common within the cerebral vasculature, and features are consistent with ischemia and infarction.
Other manifestations that are considered clinical features associated with APS, but are not diagnostic, include cardiac valve abnormalities, myocardial infarction, coronary artery disease, pulmonary hypertension, thrombocytopenia, hemolytic anemia, nephropathy, neurologic manifestations, and livedo reticularis, a lattice-like pattern of superficial veins most often found on the thighs, shins, and hands. Presence of one or more of these features, especially with laboratory criteria, raises suspicion of APS.7
Initial treatment of venous thrombosis is the same, regardless if APS is implicated. Laboratory tests to rule out APS should be performed prior to initiation of anticoagulation therapy, and other thrombophilic causes excluded. Intravenous heparin or low-molecularñweight heparin (LMWH) for at least five days should be initiated, overlapped with warfarin therapy until a target international normalized ratio (INR) of 2.0 to 3.0 is achieved and maintained.1,14,15
For long-term treatment, low-dose aspirin alone or low-intensity warfarin is ineffective in preventing recurrence. In a retrospective study among 70 patients with APS, warfarin treatment of intermediate intensity (INR 2.0 to 2.9) and high intensity (INR 3.0 or higher) significantly reduced the rate of recurrent thrombosis, whereas low-intensity treatment (INR 1.9 or less) did not confer significant protection.16 In this trial, there were five nonfatal bleeding complications. The evaluators did not report which event happened during which treatment.16
To further clarify if APS should be treated with intermediate or high-intensity warfarin, a randomized, double-blind clinical trial was performed in 114 patients with aPL and previous thrombosis. Intermediate-intensity warfarin (INR 2.0 to 3.0) was superior to high-intensity warfarin (INR 3.1 to 4.0) for thromboprophylaxis. The incidence of recurrent thrombosis was 10.7% in patients assigned to receive high-intensity warfarin and 3.4% in patients assigned to receive intermediate-intensity warfarin. Eleven patients (19%) in the intermediate-intensity group and 14 patients (25%) in the high-intensity group had at least one episode of bleeding, although the difference was not statistically significant.17
The efficacy findings suggest that intermediate-intensity warfarin is appropriate for patients with APS. Although differences in bleeding rates were not significant in this trial, higher INR targets generally increased risk for hemorrhagic complications.18
In persons with recurrent thromboses despite warfarin treatment, adjusting the warfarin dosage to target a higher INR (3.0 to 4.0) and adding low-dose aspirin are recommended.14
Normalization of the LA or aCL is not an indication to discontinue anticoagulation, because patients remain at risk for new thromboses regardless of change in titer. There is a higher risk of recurrent thromboses in the six months following discontinuation of warfarin.4 Thus, APS patients with vascular events should remain on warfarin therapy indefinitely.15
Arterial thromboembolism in APS affects the cerebral circulation, manifesting as stroke and transient ischemic attacks, and with less certainty may manifest as myocardial infarction. Treatment for patients with APS and a first ischemic stroke consists of anticoagulation with aspirin (325 mg/day) or intermediate-intensity warfarin (INR 1.4 to 2.8). This was based on a prospective cohort study performed in 1,770 patients with presence or absence of aPL, comparing intermediate-intensity warfarin and aspirin (325 mg/day) for prevention of recurrent stroke or death. The investigators found no difference in the risk of thrombotic events in patients treated with warfarin compared with aspirin, as well as no difference in the risk of bleeding.19
Treatment of APS with recurrent thrombotic events despite warfarin therapy is uncertain. These persons may be treated by increasing the target INR (2.5 to 3.5 or 3.0 to 4.0), switching from warfarin to therapeutic dosages of unfractionated heparin or LMWH, or adding an antiplatelet agent to warfarin. 2
Pregnancy losses in APS typically occur at or after the 10th week of gestation. It is hypothesized that APS-related pregnancy loss results from poor placental perfusion due to localized thrombi.6 In addition, the reduction of annexin V in the placenta (previously known as placental anticoagulant protein I) may also be an important mechanism of thrombosis and pregnancy loss in APS.20 The aPL reduce levels of annexin V and accelerate the coagulation of plasma. Elevated estrogen levels during pregnancy are also associated with increased risk of thrombosis, even in the absence of aPL.21
Women with aPL and repeated pregnancy loss, but no history of thrombosis or SLE, can achieve a similar live birth rate as that of non-aPL positive women (approximately 80%) with the use of either low-dose aspirin alone or heparin (5,000 units every 12 hours) or LMWH (enoxaparin, 1 mg/kg or 40 to 80 mg; dalteparin 5,000 units, administered once daily) plus low-dose aspirin. 2,6,22
In women with previous thrombosis and fetal loss, those who fulfill the Sapporo criteria should receive low-dose aspirin (81 mg), full anticoagulation with subcutaneous unfractionated heparin (10,000 units every 12 hours), or LMWH.14 Treatment should begin as soon as intrauterine pregnancy is documented. LMWH should be discontinued at the 36th week of gestation and replaced by unfractionated heparin. Thromboprophylaxis should be continued for six to eight weeks after delivery.23
Women who desire to become pregnant and are taking warfarin prior to pregnancy should be counseled to switch to heparin either before conception or as soon as pregnancy is confirmed to avoid the risk of warfarin embryopathy.23 Patients with high-titer aPL have about a 50% to 75% chance of fetal loss, but with aspirin and heparin the chance of full-term delivery increases 70% to 80%. 24
Intravenous immunoglobulin (IVIg) is an immune globulin currently used for the treatment of immune thrombocytopenic purpura, Guillain-BarrÈ syndrome, Kawasaki disease, and polymyositis/dermatomyositis. Its role in APS is to inhibit aPL. This may be due to the presence of anti-idiotypes to aPL within IVIg preparations or to the presence of F(ab)2 fragments from IVIg that inhibit the binding of aCL to cardiolipin in a dose-dependent manner.
IVIg infusions at varied dosages (400 mg/kg/day for five days; alternatively, 1 to 2 g/kg in divided doses over two to five days given monthly), at varied time of administration, and with concomitant therapies (e.g., heparin, aspirin), have been reported in patients with aPL who continue to lose pregnancies despite receiving low-dose aspirin and heparin.1,25 Reports have suggested that the mechanism of action of IVIg in the treatment of APS involves short-term neutralization of aPL, resulting in a long-term decrease in antibody titers.25
Caution should be observed in patients with IgA deficiency; serum IgA levels should be checked prior to IVIg to prevent severe reactions. Adverse effects may include migraine attacks, 10% increased risk of aseptic meningitis, and increased risk of urticaria, pruritus, or petechiae two to five days after infusion.25
A minority of patients may present with a life-threatening syndrome called catastrophic APS (CAPS). It is diagnosed when evidence of involvement of three or more organs within one week is confirmed by histology evidence and the presence of aPL. Venous or arterial thrombosis of large vessels is less common in patients with CAPS.6 The kidney is the organ most commonly affected, followed by the lungs, the heart, and the skin.6 Disseminated intravascular coagulation may also occur specifically in CAPS, but not in primary or secondary APS. Infections, surgical procedures, withdrawal of anticoagulant therapy, and the use of drugs such as oral contraceptives are considered precipitating factors for CAPS.
Patients with CAPS are usually treated with full anticoagulation with IV heparin, overlapped with warfarin therapy to achieve an INR of 3.0. Other agents that may have a role in treatment of CAPS include corticosteroids, IVIg, and plasmapheresis.26 With limited evidence, long-term oral anticoagulation is recommended to prevent further APS-related thrombotic events.26
APS is an autoimmune disorder that presents unique challenges in diagnosis and treatment. The revised diagnosis can be simply stated as the presence of one clinical and one laboratory criteria. In practice, the heterogeneous presentation of both clinical and laboratory findings complicates diagnosis. This disorder should always be included in differential diagnosis of persons who have coagulation defects, evidence of vascular thrombosis, and/or history of recurrent miscarriages or fetal losses. Positive laboratory testing should always be confirmed at least 12 weeks apart to verify persistence.
The heterogeneous presentation of APS also makes treatment challenging, and, in particular, research clarifying optimal therapy remains lacking. Currently, the mainstay of treatment is anticoagulation in those persons who develop an acute thrombotic event. Although indefinite duration of anticoagulation therapy is recommended, the decision to administer long-term anticoagulation certainly requires judicious clinical evaluation and risk assessment, given the potential hemorrhagic complications of anticoagulation therapy.
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