Antiphospholipid antibody syndrome (APS) is an autoantibody-mediated thrombophilic disorder that causes a hypercoagulable state and can lead to venous thromboembolism, stroke, multiple miscarriages, and other pregnancy complications (Figure 1).1-3 Definitive diagnosis is characterized by the persistent elevation of antiphospholipid antibody titers; however, recurrent arterial or venous thromboembolism (VTE) and recurrent fetal loss are clinical signs also used in diagnosis.3,4
Antiphospholipid antibodies were first discovered in 1906 in patients who tested positive serologically for syphilis.1 The antibodies are generated against cell membrane phospholipids, proteins, and other factors involved in the coagulation cascade.3,5,6
APS is considered primary if it occurs in a patient with no underlying disease and secondary if it is related to an underlying pathology such as systemic lupus erythematous (SLE). Clinical manifestations are similar in primary and secondary APS.6 Catastrophic APS is a rare, severe form of APS that can be fatal, and is defined by microvascular thrombosis leading to multiorgan failure that typically involves the brain, kidneys, and lungs.7
The clinical and laboratory diagnostic criteria for APS can be confusing.8 Consensus diagnostic criteria consist of laboratory and clinical criteria. Laboratory testing for antiphospholipid antibodies (aPL) that are associated with APS includes lupus anticoagulant, anticardiolipin IgG and IgM antibodies, and anti-beta2-glycoprotein I (anti-beta2 GPI) IgG and IgM antibodies.9,10 Clinical criteria include vascular thrombosis and pregnancy morbidity.9 At minimum, patients must meet one clinical and one laboratory criterion to be diagnosed with APS.9
This article describes APS, the difficulties in diagnosing it, clinical and laboratory criteria for diagnosis, and treatment and management options.
APS can occur in either sex but is most common in women.11 Antiphospholipid antibodies have been found in 65% to 70% of women with thrombosis in areas of the body considered unusual, such as the cerebral portal and the mesenteric and splenic veins.11 Women typically are diagnosed during their reproductive years (ages 15 to 55 years).11 Women with documented APS should not be given combination estrogen-progestin oral contraceptives because of the increased risk of thrombosis.11
Between 1% and 5% of the general population has antiphospholipid antibodies.3,9 However, only a few of these patients will develop APS, with an estimated incidence of APS being 5 new cases per 100,000 people per year and the prevalence estimated at 40 to 50 cases per 100,000 people.9 Based on existing literature, antiphospholipid antibodies are positive in about 13% of patients with a history of stroke, 11% of patients with myocardial infarction (MI), 9.5% of patients with deep vein thrombosis (DVT), and 6% of patients experiencing fetal loss.9
APS has been found to be the cause in 14% of all strokes, 11% of MIs, 10% of DVTs, and 9% of spontaneous fetal losses.12 Between 30% and 40% of patients with SLE have positive antiphospholipid antibodies; however, only about 10% of patients with SLE have been diagnosed with APS.12
The incidence of APS has been associated with the number of positive antiphospholipid antibody tests.13 More specifically, patients with all three types of antibodies (called triple positivity) have higher occurrences and recurrences of thromboembolic events.13 The annual rate of a first thromboembolic event in white patients ages 35 to 55 years without APS is 0.4%, compared with 0% to 3.8% in an asymptomatic patient with positive antiphospholipid antibodies.13 The incidence of thromboembolic events in patients positive for one antiphospholipid antibody is 1.36%, rising to 5.3% in patients with triple positivity.13
APS is an acquired autoimmune disease that is multisystemic and may occur alone or in conjunction with connective tissue disorders such as SLE or rheumatoid arthritis.14 The cause is not known, although genetic factors, such as an increased frequency of human leukocyte antigen (HLA) subsets, have been seen in patients with SLE.9
Patients must have one or more antiphospholipid antibodies and one clinical criterion for the diagnosis of APS.7 Patients with more than one positive antibody are at higher risk for thrombosis; those with triple positivity are at highest risk.7 Lupus anticoagulant binding to anti-beta2 GPI is associated with thrombosis, and anticardiolipin antibodies that recognize anti-beta2 GPI form a dependent complex that is associated with thrombosis and pregnancy complications.7
Many other mechanisms for thrombosis in patients with APS have been described, including increased tissue factor expression on white cells and endothelial cells, interference along the anticoagulation pathway of protein C, inhibition of fibrinolysis, and inhibition of annexin V binding to phospholipids.7 Other influences on thrombotic pathophysiology include the concurrent presence of other prothrombotic factors such as inherited thrombophilia, pregnancy, immobilization, surgery, and SLE.10
Patients may have transient positive antibodies and may or may not have clinical symptoms. Some patients may have persistently positive antibodies and no clinical symptoms, seronegative antibodies with clinical symptoms, or persistently positive antibodies and symptoms (APS). A “two-hit” theory also has emerged, positing that positive antibodies increase thrombotic risk (first hit) and the actual thrombotic event is triggered by an environmental risk factor (second hit) such as pregnancy, age, diabetes, smoking, obesity, or hypertension (Figure 2).12,14,15
Risk factors for APS include age (over 55 years for men and over 65 years for women), cardiovascular disease risk factors, autoimmune disease (primarily SLE), smoking, surgery, immobilization, family history of premature cardiovascular disease, oral contraceptive use, inherited thrombophilias, and pregnancy.9 About 24% of thrombotic events in women occur during pregnancy or during the postpartum period.11
Conditions clinically associated with APS include thrombocytopenia, heart valve disease, MI, chorea, levido reticularis/racemose, nephropathy, anticardiolipin IgA, anti-beta2 GPI IgA, antiphosphatidylserine antibodies, antiphosphatidylethanolamine antibodies, antibodies against prothrombin alone, and antibodies to the phosphatidylserine-prothrombin complex, but none of these are specific to APS.7,9,16
APS causes venous, arterial, or small-vessel thrombosis and can cause death.4 The thrombotic event is nonselective, affecting any vessel size and occurring in any area of the body. Most frequently, DVT, pulmonary embolus (PE), and stroke are reported.4 Patients with untreated APS are at high risk for occurrence and recurrence of these events.4
Pregnancy complications, a distinct group that differs from vascular APS, include more than three consecutive spontaneous abortions before 10 weeks gestation; at least one unexplained fetal death after 10 weeks gestation of a morphologically normal fetus; and premature birth (before the 34th week) of a normal neonate due to eclampsia, severe preeclampsia, or placental insufficiency.
Patients with recurrent spontaneous abortion and positive antibodies have a 15-fold greater risk of thromboembolic events than patients presenting with recurrent spontaneous abortion who do not have positive antibodies.14
Lupus anticoagulant is known to interfere with coagulation by prolonging the phospholipid-dependent test.7 Lupus anticoagulant is considered a nonspecific inhibitor because it can block phospholipid surfaces needed for coagulation, causing an elevated activated partial thromboplastin time (aPTT).7 However, lupus anticoagulant also has been known to increase clotting and is more strongly associated with thromboembolism than the other antiphospholipid antibodies.7 Laboratory testing should not be done during an acute thrombotic event because it could lead to false-positive results.4,7 Up to 10% of healthy people and 30% to 50% of patients with lupus are positive for lupus anticoagulant.1
WHO AND WHEN TO TEST
Testing for APS depends on the patient's clinical history and whether thrombosis or pregnancy complications may have other causes.7 Women who have experienced recurrent spontaneous abortions should be tested.7 Routine screening is not recommended in patients with ischemic stroke; however, adults under age 50 years who have had ischemic stroke should be tested.7 Patients with an unprovoked proximal DVT or PE after discontinuing anticoagulation of at least 7 days also should be tested for APS.7
Other diagnoses to consider include:
- Other hypercoagulable states such as malignancy, antithrombin III deficiency, protein C or S deficiency, factor V Leiden, prothrombin A mutation, antiprothrombin antibodies, hormone replacement therapy, and oral contraceptive use
- Atherosclerotic vascular disease including cholesterol emboli syndrome
- Systemic necrotizing vasculitis
- Disseminated intravascular coagulation
- Infective endocarditis
- Thrombotic thrombocytopenic purpura.
Patients must have one clinical criterion and one laboratory criterion or the diagnosis of APS.9
- Clinical: one or more episodes of thrombosis in any tissue or organ, confirmed by appropriate imaging studies or histopathology from samples without significant evidence of inflammation in the vessel wall
- Clinical: pregnancy complications (spontaneous abortions, unexplained fetal death, or premature birth) as described earlier
- Laboratory: positive lupus anticoagulant result on two or more tests performed at least 12 weeks apart
- Laboratory: IgG or IgM anticardiolipin antibodies in a medium or high titer (more than 40 GPL or MPL units or greater than the 99th percentile), based on two or more tests performed at least 12 weeks apart using the standard ELISA test
- Laboratory: anti-beta2-GPI IgG and IgM antibodies greater than the 99th percentile, based on two or more tests performed at least 12 weeks apart using the standard ELISA test.7,9,16
Laboratory testing for anticardiolipin antibodies and anti-beta2 glycoprotein-I antibodies poses a challenge due to the poor standardized nature of laboratory testing.10 The presence of lupus anticoagulant is more strongly associated with the risk of thromboembolism than the other criteria mentioned.6,7
The best practice for diagnosing APS is to perform a thorough clinical history and physical examination to determine if the patient meets the diagnostic criteria for APS or has hereditary thrombophilias or other causes of thrombosis or pregnancy complications.7
Other autoantibodies such as annexin V, antiphosphatidylserine, antiphosphatidylethanolamine, antibodies against prothrombin alone, antibodies to phosphatidylserine-prothrombin, and complex tissue factor expression on white cells show clinical associated features to APS, but their role has not been clearly defined as they have not been shown to be specific to APS.7,8
TREATMENT AND PREVENTION
Treatment recommendations must consider the patient's risk factors, number of positive antibodies, clinical associated factors, current clinical issues, and history of thrombotic events.12 Current best care recommendations for patients with positive antibody tests and APS are as follows:
Patients who are asymptomatic with positive antibodies do not require any specific treatment.12 Clinical associations such as valvular heart disease, hypertension, hyperlipidemia (using statins), and associated autoimmune diseases (such as SLE) should be managed and controlled.12 In patients with SLE, hydroxychloroquine may be helpful due to its intrinsic anti-inflammatory and antithrombotic properties.12 Eliminate all risk factors that are known procoagulants, such as smoking and oral hormone replacement, if present.12
Low-dose aspirin is widely used as prophylaxis; however, its effectiveness as a primary prevention treatment has not been shown.12 Clopidogrel also has been used for prevention, with positive anecdotal reports in patients with APS, but has not been proven effective.12
Prophylactic surgical placement of an inferior vena cava filter may be necessary in patients with recurrent DVT.12 Aortic valve replacement surgery is recommended for patients with severe aortic regurgitation.11 Patients with chronic forms of idiopathic thrombocytopenic purpura should undergo splenectomy for control of the resulting thrombocytopenia.11 Patients undergoing abdominal or orthopedic surgery should be placed on thromboprophylaxis.11
The mainstay treatment for thrombotic APS is heparin followed by long-term warfarin or other vitamin K antagonists.4,17 Warfarin therapy should be adjusted to a target international normalized ratio (INR) of 2 to 3 in patients with venous thrombosis and 3 for those with arterial thrombosis.1,12 Patients with recurrent thrombosis despite being on anticoagulation should have a target INR between 3 and 4.12 In patients refractory to warfarin treatment alone, warfarin and aspirin combination treatment is suggested. Open-label clinical trials of oral direct thrombin and antifactor Xa inhibitors are being conducted in patients with APS.17
The risk of thrombotic recurrence has been shown to be greatest during the 6-month period following discontinuation of warfarin therapy.1 Therefore, indefinite anticoagulation treatment is recommended in patients with APS and a history of thromboembolism.1,6,12
Treatment in pregnancy
Pregnancy is considered high-risk in women with APS and should be treated as such.11 Provide patient education and counseling about the signs and symptoms of thromboembolism, preeclampsia, and decreased fetal movement.11 The likelihood of a viable pregnancy in women with APS and the correct treatment is 75% to 80%.18 The use of novel antiplatelet agents has not been well studied in this subgroup.1,17,18
In women attempting pregnancy without a prior thromboembolic event, no standard therapy is available and anticoagulation may decrease recurrent pregnancy complications.11 In these cases, low-dose aspirin (81 mg daily) in addition to prophylactic doses of heparin is superior to aspirin alone.11
In women with marked thrombocytopenia, epidural anesthesia is not recommended.11 In the postpartum period, the mother can be switched to warfarin with a target INR of 3.11 Referral to a hematology specialist is appropriate in either case.1
Early diagnosis and aggressive therapies are essential in catastrophic APS because of its extremely high mortality. For patients with catastrophic APS, treatment with plasma exchange or immune globulin in addition to corticosteroids, anticoagulant therapy, and/or rituximab has been recommended.1,4
Asymptomatic patients with positive antibodies
Lupus anticoagulant antibodies may be detected in asymptomatic patients who do not meet clinical criteria for APS. This is due to the common use of aPTT laboratory testing in clinical practice. In such cases, a detailed history should be taken to assess for any missed cases of APS due to missed positive clinical criteria. Although asymptomatic patients with positive antibodies may be at higher risk for thromboembolism, there is no agreement on the role of, or recommendations for, prophylactic treatment in this subgroup.6
Follow pediatric thromboembolism management guidelines for children with VTE associated with antiphospholipid antibodies.6 Children should be managed by a pediatrician with expertise in thromboembolism management. Otherwise, an adult or pediatric hematologist is recommended for consultation and care.6
Several controversies continue to surround the diagnosis and treatment of APS due to the unpredictable expression of the disease and its effects.
Patients who may have transient positive antibodies (with or without clinical symptoms) remain the most controversial. There is no concrete information or evidence on the significance of transient elevation of antiphospholipid antibodies in patients with no clinical symptoms, and treating asymptomatic patients with positive antibodies is not recommended. Prophylactic treatment of asymptomatic patients with positive antibodies likely is not necessary unless clinical symptoms emerge due to a “second hit” triggered by another disease, such as an infection. The significance of positive antibodies in patients with clinically associated diseases that occur commonly in the general population remains unclear. The presence of antiphospholipid antibodies alone does not have clear implications on the management of these conditions.
However, further research needs to be performed to include patients with transient elevation of antibodies and seronegative patients who have clinical symptoms, as associated antiphospholipid antibodies not yet reported may be causing the patient's symptoms. Research will help establish guidelines on prophylactic treatment for the prevention of thrombosis or pregnancy complications in these patients. Diagnosing a patient with transient antibody elevations may be easy to do over the continuum of their health history but may prove to be difficult to diagnose early in the disease.
Another consideration that warrants further investigation is whether the transient elevation of antibodies with clinical symptoms is some sort of prelude to other potentially associated autoimmune diseases, such as rheumatoid arthritis, which may appear months to years after the initial detection of elevated antiphospholipid antibodies.
In the case of asymptomatic women (pregnant or not) with persistently elevated antibodies, pharmacologic treatment is not recommended.4
Further research also is needed to determine if associated antibody, medication, or disease triggers can be targeted to prevent the thrombosis cascade from starting. This may be achieved through continued development of the global APS score, originally developed in patients with SLE to stratify disease severity.15
Finally, the special consideration groups: pregnant women, children, and men with recurrent VTE or stroke before at 50 years, need to be studied further in order to establish a consensus guideline on treatment and prevention therapies. This is due to little research being available on these special groups. More information would help to determine the expression of the disease and clarify the link for a potential hereditary component to the disease.
The key elements to diagnosing APS are at least one positive clinical finding and one positive laboratory finding found on two occasions at least 12 weeks apart. Treatment of APS is appropriate and indefinite anticoagulation. For patients with positive antibodies and no clinical symptoms, no treatment is recommended. Prevention of APS focuses on treating those clinically associated diseases, such as hypertension and hyperlipidemia, as well as avoiding medications known to trigger APS events under the “second hit” theory.