Antiphospholipid Syndrome

Practice Essentials

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder that manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss.^[1] Characteristic laboratory abnormalities in APS include persistently elevated levels of antibodies directed against membrane anionic phospholipids (ie, anticardiolipin [aCL] antibody, antiphosphatidylserine) or their associated plasma proteins, (predominantly beta-2 glycoprotein I [apolipoprotein H]); and/or evidence of a circulating anticoagulant. See Presentation and Workup.

Some patients have isolated APS, with no evidence of any definable associated disease. In other patients, APS occurs in association with systemic lupus erythematous (SLE) or another rheumatic or autoimmune disorder. Traditionally, these are referred to as primary or secondary APS, respectively. Although antiphospholipid (aPL) antibodies are clinically linked to APS, whether they are involved in the pathogenesis or are an epiphenomenon is unclear. Up to 5% of healthy individuals are known to have aPL antibodies.

The development of aPL antibodies has been described in association with thrombosis in patients with COVID-19, and in a cohort study from France, lupus anticoagulant was detected in a large percentage of patients with severe COVID-19. However, it is not yet known whether the aPL antibodies in these patients play a role in the thrombosis that occurs in COVID-19 cases, or merely represent an association.^[2]

In general, treatment regimens for APS must be individualized according to the patient's current clinical status and history of thrombotic events. Asymptomatic individuals in whom blood tests show aPL antibodies do not require specific treatment. For patients with APS, prophylaxis is needed during surgery or hospitalization, as is management of any associated autoimmune disease. Low-dose aspirin is used widely in this setting; although its effectiveness remains unproven. For thrombosis, perform full anticoagulation with intravenous or subcutaneous heparin followed by warfarin therapy. See Treatment.

For discussion of APS in children, see Pediatric Antiphospholipid Antibody Syndrome. For discussion of obstetric APS, see Antiphospholipid Syndrome and Pregnancy.

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Pathophysiology

In APS, the homeostatic regulation of blood coagulation is altered; however, the mechanisms of thrombosis are not well defined. One hypothesis postulates a defect in cellular apoptosis, which exposes membrane phospholipids to the binding of various plasma proteins, such as beta-2 glycoprotein I. Once bound, a phospholipid-protein complex is formed and a neoepitope is uncovered, which subsequently becomes the target of autoantibodies. Evidence suggests that oxidized beta-2 glycoprotein I is able to bind to and activate dendritic cells in a manner similar to activation triggered by Toll-like receptor 4 (TLR-4), which could amplify the production of autoantibodies.^{[1, 3]}

Other proposed mechanisms for the hypercoagulable effect of aPL antibodies, which may or may not depend on beta-2 glycoprotein I, include the following:

• Production of antibodies against coagulation factors, including prothrombin, protein C, protein S, and annexins
• Activation of platelets to enhance endothelial adherence
• Activation of vascular endothelium, which in turn facilitates the binding of platelets and monocytes
• Reaction of antibodies to oxidized low-density lipoprotein, thus predisposing to atherosclerosis and myocardial infarction (MI)

Complement activation has been increasingly recognized as possibly having a significant role in the pathogenesis of APS. Failure of the normal complement-regulating mechanisms can result in uncontrolled complement activation, leading to complement-mediated direct cellular injury and thrombosis.^[4] Evidence from murine models suggests that aPL-mediated complement activation may be a primary event in pregnancy loss.^{[3, 5]} Rare germline variants in complement regulatory genes have been found in 60% of patients with catastrophic APS, compared with 21.8% of patients with thrombotic APS and 23.3% of normal controls.^[6]

Clinically, the series of events that leads to hypercoagulability and recurrent thrombosis can affect virtually any organ system, including the following:

• Peripheral venous system (deep venous thrombosis [DVT])
• Peripheral nervous system (peripheral neuropathy, including Guillain–Barré syndrome)
• Hematologic (thrombocytopenia, hemolytic anemia)
• Obstetric (pregnancy loss, eclampsia)
• Pulmonary (pulmonary embolism [PE], pulmonary hypertension)
• Dermatologic (livedo reticularis, purpura, infarcts/ulceration)
• Cardiac (Libman-Sacks valvulopathy, MI, diastolic dysfunction)
• Ocular (amaurosis, retinal thrombosis)
• Adrenal (infarction/hemorrhage)
• Musculoskeletal (avascular necrosis of bone)
• Renal (thrombotic microangiopathy)

The kidney is a major target organ in APS. Nephropathy in APS is characterized by small-vessel vaso-occlusive lesions associated with fibrous intimal hyperplasia of interlobular arteries, recanalizing thrombi in arteries and arterioles, and focal atrophy.^[7]

A “two-hit” theory has been proposed in which a second risk factor (age, hypertension, diabetes, obesity, smoking, pregnancy, surgery, infection, other genetic hypercoagulable state) incites the thrombotic effects of aPL in a patient with underlying genetic predisposition.^[8]

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Etiology

APS is an autoimmune disorder of unknown cause. The search for possible triggers has uncovered a wide array of autoimmune or rheumatic diseases, infections, and drugs that are associated with the lupus anticoagulant or anticardiolipin antibodies. These associations may ultimately provide a clue to the etiology of APS.

A considerable percentage of persons with certain autoimmune or rheumatic diseases also have aPL antibodies. Common autoimmune or rheumatic diseases and the percentage of affected patients with aPL antibodies are as follows (note that these represent percentages of patients with aPL antibodies, rather than the clinical syndrome of APS^[9] ):

• SLE - 25-50%
• Sjögren syndrome - 42%
• Rheumatoid arthritis - 33%
• Immune thrombocytopenia - 30%
• Psoriatic arthritis - 28%
• Systemic sclerosis - 25%
• Mixed connective-tissue disease - 22%
• Polymyalgia rheumatica or giant cell arteritis - 20%
• Behçet syndrome - 20%
• Autoimmune hemolytic anemia - Unknown

Infections associated with APS include the following^[10] :

• Syphilis
• Hepatitis C 
• HIV infection
• Human T-cell lymphotrophic virus type 1 infection
• Malaria
• Bacterial septicemia

Drugs associated with APS include the following:

• Cardiac - Procainamide, quinidine, propranolol, hydralazine
• Neuroleptic or psychiatric - Phenytoin, chlorpromazine
• Other - Interferon alfa, quinine, amoxicillin

In addition, certain vaccines have been associated with APS. For example, vaccination with tetanus toxoid may trigger the formation of antibodies that cross-react with beta-2 glycoprotein I, due to molecular mimicry between the two molecules.^[11]

 Genetic predisposition may be involved, as follows:

• Relatives of persons with known APS are more likely to have aPL antibodies. One study showed a 33% frequency.
• An association has been found between aCL antibody and carriage of certain HLA genes, including DRw53, DR7 (mostly in people of Hispanic origin), and DR4 (mostly in Whites).^[12]

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Epidemiology

The frequency of APS is likely similar in the United States and internationally. The actual frequency of APS in the general population is unknown. The annual incidence of APS has been estimated at approximately 5 cases per 100,000 persons, and the prevalence is approximately 40-50 cases per 100,000 persons.^{[13, 14]}

One to 5% of healthy individuals have aPL antibodies. aPL antibodies tend to be found more frequently in elderly persons; thus, positive titer results should be interpreted with caution in this population. aPL antibodies are found in approximately 30-40% of patients with SLE, but only about 10% have APS.^[15] Approximately half of APS cases are not associated with another rheumatic disease. In a study of 100 patients with confirmed venous thrombosis and no history of SLE, anticardiolipin antibodies were found in 24% and lupus anticoagulant in 4%.

The approximate frequency of positive aPL titers in patients with other disorders is as follows^[16] :

• Stroke: 13%
• Myocardial infarction: 11%
• Deep venous thrombosis: 9.5%
• Pregnancy morbidity: 6%

 Race-, Sex-, and Age-related Demographics

No defined racial predominance for primary APS has been documented, although SLE is more common in African- American and Hispanic populations.

A female predominance has been documented, particularly for secondary APS. This parallels the association of APS with SLE and other connective-tissue diseases, which also have a female predominance.

APS is more common 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. In an international registry of pediatric APS cases, patients without associated rheumatic disease were younger and had a higher frequency of arterial thrombotic events, whereas patients with associated rheumatic disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations.^[17]

Mortality/Morbidity

APS may contribute to an increased frequency of stroke or MI, especially in younger individuals. Strokes may develop secondary to in situ thrombosis or embolization that originates from the valvular lesions of Libman-Sacks (sterile) endocarditis, which may be seen in patients with APS. Cardiac valvular disease may be severe enough to require valve replacement. Recurrent pulmonary emboli or thrombosis can lead to life-threatening pulmonary hypertension.

Catastrophic APS (CAPS) is a rare, serious, and often fatal manifestation characterized by multiorgan infarctions over a period of days to weeks. Mortality rates of 50% have been reported; however, with triple therapy (anticoagulation, corticosteroids, plasma exchange and/or intravenous immunoglobulin) data from an international registry showed a mortality rate of 28.6%.^[18]

Late spontaneous fetal loss (second or third trimester) is common; however, it can occur at any time during pregnancy. Recurrent early fetal loss (< 10 weeks’ gestation) is also possible.

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History

Antiphospholipid syndrome (APS) is a heterogeneous disorder in terms of clinical manifestations and range of autoantibodies. Two classification systems for APS have been published: the widely recognized Revised Sapporo Criteria, an international consensus statement published in 2006, requires at least one clinical criterion and one laboratory criterion for the diagnosis of APS^[19] (see Workup/Laboratory Studies); the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR), published in 2023, includes six clinical criteria and two laboratory criteria, with diagnosis based on points (see DDx/Diagnostic Considerations).

In the Revised Sapporo Criteria, the clinical criteria consist of vascular thrombosis and pregnancy morbidity. Vascular thrombosis is defined as one or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ that is confirmed by findings from imaging studies, Doppler studies, or histopathology (see Workup/Histologic Findings). Of note, superficial thrombosis is not included as a clinical criterion.

Thrombosis may involve the cerebral vascular system, coronary arteries, pulmonary system (emboli or thromboses), arterial or venous system in the extremities, hepatic veins, renal veins, ocular arteries or veins, or adrenal glands. Investigation is warranted if a history of deep venous thrombosis (DVT), pulmonary embolism (PE), acute ischemia, myocardial infarction (MI), or stroke (especially when recurrent) is present in a younger individual (males < 55 y; females < 65 y) or in the absence of other risk factors.

Pregnancy morbidity is defined as the following:

• One or more spontaneous abortions at > 10 weeks’ gestation
• One or more premature births of a morphologically healthy neonate at or before 34 weeks’ gestation because of severe preeclampsia or eclampsia or severe placental insufficiency
• Three or more unexplained, consecutive, spontaneous abortions at < 10 weeks’ gestation

Other antiphospholipid (aPL)–associated clinical features recognized by the 2006 consensus statement but not included in the criteria include cardiac valve disease, livedo reticularis, thrombocytopenia, nephropathy, and neurologic manifestations.

Thus, history of any of the following should raise suspicion for APS:

• Thrombosis (eg, DVT/PE, MI, transient ischemic attack [TIA], or stroke, especially if recurrent, at an early age, in unusual anatomic locations such as upper extremity DVT, or in the absence of other known risk factors)
• Miscarriage (especially late trimester or recurrent) or premature birth
• History of heart murmur or cardiac valvular vegetations
• History of hematologic abnormalities, such as thrombocytopenia or hemolytic anemia
• History of nephropathy
• Non-thrombotic neurologic symptoms, such as migraine headaches, chorea, seizures, transverse myelitis, Guillain-Barré syndrome, or dementia (rare)^[20]
• Unexplained adrenal insufficiency
• Avascular necrosis of bone in the absence of other risk factors
• Pulmonary hypertension
• Diffuse pulmonary hemorrhage

Catastrophic antiphospholipid syndrome

A rare but but life-threatening variant of APS is catastrophic APS (CAPS), which is characterized by involvement of three or more organs in less than a week. This may include renal, cerebral, pulmonary, cardiac, hepatic, adrenal involvement, or peripheral gangrene. This may be precipitated by infections, surgical interventions, drugs, or anticoagulation withdrawal. Although CAPS accounts for less than 1% of APS cases, mortality ranges from 37% to 50%.^[4]

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Physical

Cutaneous manifestations include the following:

• Livedo reticularis (see image below)

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  Antiphospholipid syndrome. Livedo reticularis.

   

  

   
• Superficial thrombophlebitis
• Leg ulcers
• Painful purpura
• Splinter hemorrhages

Venous thrombosis–related findings include the following:

• Leg swelling (DVT)
• Ascites (Budd-Chiari syndrome)
• Tachypnea (pulmonary embolism)
• Peripheral edema (renal vein thrombosis)
• Abnormal funduscopic examination results (retinal vein thrombosis)

Arterial thrombosis–related findings include the following:

• Abnormal neurologic examination results (eg, stroke)
• Digital ulcers

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  Antiphospholipid syndrome. Arterial thrombosis resulting in ischemia and necrosis of the foot.

   

  

   
• Signs of myocardial infarction
• Heart murmur (frequently aortic) or mitral insufficiency (Libman-Sacks endocarditis)
• Abnormal funduscopic examination results (retinal artery occlusion)

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Laboratory Studies

The following laboratory tests should be considered in a patient suspected of having antiphospholipid syndrome (APS), as patients with APS may have abnormal results on one or more of them:

• Anticardiolipin (aCL) antibodies (IgG, IgM)
• Anti–beta-2 glycoprotein I antibodies (IgG, IgM)
• Activated partial thromboplastin time (aPTT)
• Tests for lupus anticoagulant (LA; eg, dilute Russell viper venom time [DRVVT]; a threshold of approximately 1.6 for the DRVVT ratio has been recommended for helping discriminate APS from non-APS^[22] )
• Serologic test for syphilis (false-positive result in APS)
• Complete blood cell count (CBC); may show thrombocytopenia, hemolytic anemia

The hallmark laboratory test result that defines APS is the presence of antiphospholipid (aPL) antibodies or abnormalities in phospholipid-dependent tests of coagulation.

In addition to the clinical criteria listed in Presentation/History, the 2006 Revised Sapporo Criteria required the presence of at least one of the following laboratory criteria for the classification of APS^[19] :

• Presence of LA in plasma on two or more occasions at least 12 weeks apart
• Presence of moderate to high levels of aCL (IgG or IgM) in serum or plasma (ie, > 40 IgG phospholipid units (GPL)/mL or IgM phospholipid units (MPL)/mL or > 99th percentile) on two or more occasions at least 12 weeks apart
• Presence of moderate to high levels of anti–beta-2 glycoprotein I antibodies (IgG or IgM) in serum or plasma (> 99th percentile) on two or more occasions at least 12 weeks apart

The 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria include two laboratory domains: positive findings on aPL testing with a coagulation-based functional assay (lupus anticoagulant test [LAC]) or a solid phase assay (anti-cardiolipin [aCL] enzyme-linked immunosorbent assay (ELISA) and/or anti–β₂-glycoprotein-I antibody [aβ₂GPI] ELISA [persistent]).^[21] See DDx/Diagnostic Considerations for ACR/EULAR scoring.

aCL antibodies react primarily to membrane phospholipids, such as cardiolipin and phosphatidylserine. Of the 3 known isotypes of aCL (ie, IgG, IgM, IgA), IgG correlates most strongly with thrombotic events. Cardiolipin is the dominant antigen used in most serologic tests for syphilis; consequently, these patients may have a false-positive test result for syphilis.

The literature suggests that an abnormal LA finding is the laboratory test result that indicates the strongest risk for thrombosis.^{[8, 22]} LA is directed against plasma coagulation molecules. In vitro, this interaction results in the paradoxical prolongation of clotting assays, such as activated partial thromboplastin time (aPTT), kaolin clotting time, and DRVVT. Next, normal platelet-poor plasma is mixed with the patient's plasma; failure of the mixing study to correct the prolonged clotting time rules out clotting factor deficiency. Finally, phospholipid may be added to the patient's plasma; if this normalizes the clotting time, it confirms that LA is present.^[23]

Currently, there is much investigation into risk-stratifying patients based on aPL profile, aPL titers, associated autoimmune disease, and other cardiovascular risk factors. "Triple-positive" patients (LA, anti-beta-2 glycoprotein antibodies, aCL antibodies) are at highest risk for thrombosis or abnormal pregnancy, and possibly for recurrence.^[8] Standardized scoring systems such as the Global Antiphospholipid Syndrome Score (GAPSS) are being developed.

A study of 97 pregnancies in women with a past history of APS concluded that  aPL antibodiy profiling to determine obstetric risk is best performed during the first trimester of pregnancy. Latino et al reported that risk categorization performed during pregnancy predicted pregnancy outcome more accurately than categorization performed before pregnancy (91.8% vs 82.5%, respectively).^[24]

Other tests

Thrombocytopenia is fairly common in patients with APS (22% at presentation, 30% cumulatively) and is therefore associated with paradoxical thrombosis. However, patients with platelet counts of less than 50,000/µL may have an increased risk of bleeding. Hemolytic anemia has been well described in patients with APS and is associated with the presence of IgM aCL antibodies.

A low antinuclear antibody level may be present and does not necessarily imply coexisting SLE.

Additional antibodies directed against phospholipid/phospholipid-protein complexes for which testing may be useful in selected cases (seronegative APS, because they are not part of the 2006 consensus criteria) include the following^{[25, 26, 16, 27]} :

• IgA aCL
• IgA beta-2 glycoprotein I
• Anti-phosphatidylserine antibodies
• Anti-phosphatidylethanolamine antibodies
• Anti-prothrombin antibodies
• Antibodies against the phosphatidylserine-prothrombin complex

For further information, see Antiphospholipid Antibodies.

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Imaging Studies

Imaging studies are helpful for confirming a thrombotic event. Doppler ultrasound studies are recommended for possible detection of deep venous thrombosis (DVT). Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the following may be used:

• Brain (for stroke)
• Chest (for pulmonary embolism)
• Abdomen (for Budd-Chiari syndrome)

Two-dimensional echocardiography findings may demonstrate asymptomatic valve thickening, vegetations, or valvular insufficiency. Aortic or mitral insufficiency is the most common valvular defect found in persons with Libman-Sacks endocarditis.

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Histologic Findings

In contrast to the findings in inflammatory autoimmune diseases, histologic studies of skin or other involved tissue in APS reveal a noninflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic vasculitis. Similarly, biopsy samples from affected kidneys demonstrate glomerular and small arterial microthrombi, leading to fibrosis, tubule thyroidization, focal cortical atrophy and glomerular sclerosis.^[28]

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Medical Care

Patients with antiphospholipid syndrome (APS) may be evaluated in an outpatient setting. Inpatient evaluation is required if the patient presents with a significant clinical event. Patients with catastrophic APS (CAPS) require intense observation and treatment, often in an intensive care unit.

In general, treatment regimens for APS must be individualized according to the patient's current clinical status and history of thrombotic events. Asymptomatic individuals in whom blood test findings are positive do not require specific treatment.

Prophylactic therapy

Eliminate other risk factors, such as oral contraceptives, smoking, hypertension, or hyperlipidemia. Prophylactic anticoagulation is needed during surgery or hospitalization. Management of any associated autoimmune disease is necessary.

In patients who have antiphospholipid antibodies but no history of thrombosis or pregnancy morbidity, antithrombotic therapy is not routinely used as primary thrombosis prevention. However, low-dose aspirin is used in this setting; however, the effectiveness of low-dose aspirin as primary prevention for APS remains unproven.^[16] Clopidogrel has anecdotally been reported to be helpful in persons with APS and may be useful in patients allergic to aspirin.

In patients with systemic lupus erythematosus (SLE), consider hydroxychloroquine, which may have intrinsic antithrombotic properties.

Consider the use of statins, especially in patients with hyperlipidemia. Guidelines from the European Alliance of Associations for Rheumatology (EULAR; formerly the European League Against Rheumatism), citing a lack of studies of cardiovascular risk management in patients with APS, recommend managing hyperlipidemia and hypertension in these patients according to recommendations for the general population.^[29]

Treatment of thrombosis

Perform full anticoagulation with intravenous or subcutaneous heparin followed by warfarin therapy. Based on the most recent evidence, a reasonable target for the international normalized ratio (INR) is 2.0-3.0 for venous thrombosis and 3.0 for arterial thrombosis. Patients with recurrent thrombotic events may require an INR of 3.0-4.0. For severe or refractory cases, a combination of warfarin and aspirin may be used. Treatment for significant thrombotic events in patients with APS is generally lifelong.

Direct oral anticoagulants (ie, direct thrombin inhibitors and factor Xa inhibitors such as rivaroxaban) have been used in patients with warfarin intolerance/allergy or poor anticoagulant control.^{[16, 30]} However, studies of these agents in APS patients have largely proved disappointing.

In the Rivaroxaban for Antiphospholipid Syndrome (RAPS) trial—a controlled, open-label, phase II/III non-inferiority trial in 116 APS patients—the percentage change in endogenous thrombin potential at 42 days for rivaroxaban was inferior to that of warfarin. However, because no thromboembolic events occurred over the 210‐day follow‐up in either group, the investigators concluded that rivaroxaban might be an effective and safe alternative in patients with APS and previous venous thromboembolism (VTE).^[31]

A cohort study in 176 APS patients followed for a median of 51 months reported an increased risk of recurrent thromboembolic events and recurrent VTE alone in patients receiving direct oral anticoagulants compared with those receiving warfarin. No differences were found between rivaroxaban and apixaban or among patients with single-positive, double-positive, and triple-positive APS.^[32]

The phase III Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPS) trial, which was conducted in high-risk APS patients triple-positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype, was terminated prematurely after the enrollment of 120 patients because of an excess rate of arterial thromboembolic events in patients on rivaroxaban: 12% (4 ischemic strokes and 3 myocardial infarctions) versus 0% in patients on warfarin, after 569 days’ follow‐up.^[33]

In 2019, the European Medicines Agency (EMA) issued a guidance statement recommending against the use of direct-acting oral anticoagulants (including rivaroxaban, apixaban, edoxaban, and dabigatran etexilate) for patients with a history of thrombosis who are diagnosed with APS, in particular those that are triple positive. This poses a challenge for clinicians, however, because current guidelines recommend direct oral anticoagulants for treatment of VTE. A proportion of patients with a first unprovoked VTE will have antiphospholipid antibodies, and some of those will have APS. However, when a patient presents with unprovoked VTE it is impossible to know whether APS is present, as the diagnosis of APS requires testing on two or more occasions at least 12 weeks apart.^[34]

Rituximab can be considered for recurrent thrombosis despite adequate anticoagulation. A nonrandomized prospective study showed rituximab to be effective for noncriteria aPL manifestations (ie, thrombocytopenia and skin ulcers).^[8]

Obstetric considerations

Guidelines from the American College of Obstetricians and Gynecologists (based primarily on consensus and expert opinion [level C]) include the following recommendations^[35]

• Women with APS who have a history of thrombosis in previous pregnancies should receive prophylactic anticoagulation during pregnancy and for 6 weeks postpartum.
• For women with a history of APS and prior thrombosis, anticoagulation with therapeutic-dose low molecular weight heparin (LMWH) and low-dose aspirin is recommended. After delivery, long-term anticoagulation may be switched back to warfarin.
• For women with a history of APS without thrombosis but with prior pregnancy loss, prophylactic-dose LMWH and low-dose aspirin are recommended. Therapy is withheld at the time of delivery and is restarted after delivery, continuing for 6 weeks postpartum.

EULAR has published recommendations for women's health and the management of family planning, assisted reproduction, pregnancy, and menopause in patients with SLE and/or APS. EULAR also recommends anticoagulation during pregnancy for patients with APS, with the drug and dose depending on individual risk profile.^[36]

Warfarin is contraindicated in pregnancy. Breastfeeding women may use heparin and warfarin.

Corticosteroids have not been proven effective for persons with primary APS, and they have been shown to increase maternal morbidity and fetal prematurity rates.

Unfortunately, current treatment fails to prevent complications in 20-30% of APS pregnancies.^{[37, 38]} Retrospective clinical studies suggest that treatment with hydroxychloroquine may help prevent pregnancy complications in women with aPL and APS, and this strategy is currently being studied in a randomized controlled multicenter trial (HYPATIA).^[38] In patients with a history of SLE and APS, hydroxychloroquine should be used during pregnancy.

See also Antiphospholipid Syndrome and Pregnancy.

Catastrophic antiphospholipid syndrome

Patients with catastrophic antiphospholipid syndrome (CAPS) are generally very ill, often with active SLE.^[39] The condition is too rare to support clinical trials, but improved mortality has been reported with triple therapy consisting of anticoagulation, corticosteroids, and plasma exchange and/or intravenous immunoglobulin.^[18] In addition, attention should be paid to associated disorders (eg, infection, SLE). Cyclophosphamide has been used in cases associated with SLE, although its use in first-trimester pregnancy increases risk of fetal loss.^{[36, 39]} In refractory or relapsing cases, rituximab and eculizumab have been used.^[39]

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Surgical Care

Placement of an inferior vena cava (IVC) filter may be considered in patients with APS who require cessation of anticoagulation or who continue to experience thrombotic complications despite maximal anticoagulation. Experts recommend avoiding IVC filters in the setting of acute APS, due to reports of adverse events including IVC thrombosis and pulmonary embolus. Baig et al evaluated the use of retrievable IVC filters in five patients with APS and concluded that retrievable IVC filters can be safely placed and removed in such patients, even during anticoagulation.^[40]  

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Consultations

Consultations may include the following:

• Rheumatologist
• Hematologist
• Neurologist, cardiologist, pulmonologist, hepatologist, ophthalmologist (depending on clinical presentation)
• Obstetrician with experience in high-risk pregnancies

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Medication Summary

In deciding whether to initiate anticoagulant prophylaxis for patients with antiphospholipid syndrome (APS), the benefits of these agents must be weighed carefully against their significant risks. Life-long treatment with warfarin (see Treatment) is standard for patients who experience recurrent thrombotic events.

Heparin therapy may be administered in several regimens, as follows:

• Thrombotic events are initially treated with intravenous infusion of unfractionated heparin or therapeutic doses of subcutaneous low molecular weight heparin (LMWH) and low-dose aspirin.
• Subcutaneous LMWH (enoxaparin [Lovenox]) may also be used for obstetric or thrombosis prophylaxis. Lower doses (20-40 mg/d subcutaneously) are used to prevent fetal loss, while higher doses (1 mg/kg q12h or 1.5 mg/kg/d) are used for thrombosis prophylaxis in patients (pregnant or nonpregnant) who have had prior thrombotic events.

Patients who require heparin administration throughout pregnancy should receive calcium and vitamin D supplementation to help avoid heparin-induced osteoporosis. When monitoring heparin therapy, note that the activated partial thromboplastin time (aPTT) may be unreliable in the presence of circulating antiphospholipid (aPL) antibodies with a baseline elevated aPTT. In this case, factor Xa testing may be helpful.

Hydroxychloroquine has antithrombotic properties and may be considered in the prophylactic treatment of a patient with SLE and a positive aPL antibody test result.^[29] The use of hydroxychloroquine and intravenous immunoglobulin (IVIG) has been associated with good outcomes in pregnant women with APS who develop recurrent episodes of thrombosis or catastrophic APS (CAPS) despite receiving adequate antithrombotic treatment.^[39]

In addition to full anticoagulation, plasma exchange and corticosteroids are generally used in the treatment of CAPS. IVIG or cyclophosphamide may be considered in selected patients with CAPS. However, cyclophosphamide increases the risk of first-trimester fetal loss, so its use in pregnant women should be reserved for severe, life-threatening or refractory manifestations during the second or third trimester.^[35]

Statins have been suggested to have potential antithrombotic effects. Statins are recommended for APS patients with hyperlipidemia and, possibly, in aPL patients with recurrent thromboses despite adequate anticoagulation.^[29]

Rituximab has shown benefit in controlling severe thrombocytopenia, skin ulcers, and cognitive dysfunction that can be associated with APS.^[29]

Case reports have described the use of eculizumab, a humanized monoclonal antibody against C5 complement protein, in CAPS, and in aPL-positive patients undergoing kidney transplantation.^[41]

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Warfarin (Coumadin)

• Dosing, Interactions, etc.

Clinical Context:  Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Long-term warfarin is DOC for APS in patients with recurrent thrombotic events. Titrated dose suggested to maintain INR in therapeutic range (see above).

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Enoxaparin (Lovenox)

• Dosing, Interactions, etc.

Clinical Context:  LMWH. Most experience; other LMWH preparations available.

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Heparin

• Dosing, Interactions, etc.

Clinical Context:  Used in inpatient settings as continuous infusion during conversion to warfarin therapy until a therapeutic INR is achieved. May be administered SC as substitute for warfarin during attempted pregnancy or for temporary anticoagulation during warfarin loading in outpatient setting.

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Aspirin (Anacin 81, Ascriptin, Bayer Aspirin)

• Dosing, Interactions, etc.

Clinical Context:  Although not proven effective when used alone, most clinicians use aspirin with SC heparin in pregnant patients with APS. Begin aspirin as soon as conception is attempted.

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Class Summary

Standard therapy for thrombosis commonly consists of intravenous heparin followed by warfarin. Treatment of a pregnant patient with a history of recurrent fetal loss is controversial but generally includes subcutaneous heparin and aspirin.

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Hydroxychloroquine (Plaquenil)

• Dosing, Interactions, etc.

Clinical Context:  Most common antimalarial used in APS, mostly because of excellent safety profile.

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Class Summary

As prophylactic therapy, these agents may have an additional anticoagulant effect in patients with SLE.

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Cyclophosphamide (Cytoxan, Neosar)

• Dosing, Interactions, etc.

Clinical Context:  Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Has not been shown to be effective in APS.

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Class Summary

Consider immunosuppressive agents in select cases (eg, refractory APS, CAPS).

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Prednisone (Deltasone, Orasone, Sterapred)

• Dosing, Interactions, etc.

Clinical Context:  Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Useful in treating cytopenias.

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Class Summary

In selected cases with specific nonthrombotic autoimmune manifestations (eg, clinically significant thrombocytopenia), corticosteroids may be considered.

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Intravenous immune globulins, 5% (Gammagard, Gamimune)

• Dosing, Interactions, etc.

Clinical Context:  Following features may be relevant to efficacy: neutralization of circulating myelin antibodies through antiidiotypic antibodies, down-regulation of proinflammatory cytokines (including IFN-gamma), blockade of Fc receptors on macrophages, suppression of helper/inducer T and B cells and augmentation of suppressor T cells, blockade of the complement cascade, promotion of remyelination, and 10% increase in CSF IgG. May be effective in APS.

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Class Summary

These agents interfere with processes that promote immune reactions resulting from diverse stimuli.

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Further Outpatient Care

Subsequent outpatient care includes the following:

• Carefully monitor medication doses and the international normalized ratio (INR) if applicable.
• Closely observe the patient for clinical events.
• Ensure the care of any underlying connective-tissue disease.

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Transfer

For treatment of seriously ill patients with catastrophic antiphospholipid syndrome (CAPS), transfer the patient to a setting where plasma exchange can be performed or where intravenous immunoglobulin or cyclophosphamide can be administered if needed.

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Deterrence/Prevention

Instruct the patient to avoid smoking.

Inform the patient to avoid oral contraceptives or estrogen replacement therapy.

Ensure that the patient avoids any prolonged immobilization.

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Complications

Permanent functional disability or death can occur at a relatively young age. Complications may include the following:

• Stroke
• Myocardial infarction
• Pulmonary hypertension
• Kidney failure^[42]

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Prognosis

With appropriate medication and lifestyle modifications, most individuals with primary antiphospholipid syndrome (APS) lead normal healthy lives. However, subsets of patients continue to have thrombotic events despite aggressive therapies. In these patients and in patients with catastrophic APS, the disease course can be devastating, often leading to significant morbidity or early death.

In large European cohort studies, 10-year survival is approximately 90-94%.^[43]

A retrospective study suggested that hypertension or medium-to-high titers of IgG anticardiolipin antibody are risk factors for a first thrombotic event in asymptomatic patients with antiphospholipid (aPL) antibodies.^[44]  Primary prophylaxis against thrombosis appears to offer significant protection in such cases. Annual incidence of first thrombosis is approximately 0-5% in patients with a positive aPL test without previous thrombosis.^[16]

Patients with secondary APS carry a prognosis similar to that of patients with primary APS; in the former, however, morbidity and mortality may also be influenced by these patients' underlying autoimmune or rheumatic condition. In patients with SLE and APS, aPL antibodies have been associated with neuropsychiatric disease and have been recognized as a major predictor of irreversible organ damage.

Women with aPL antibodies who experience recurrent miscarriages may have favorable prognoses in subsequent pregnancies if treated with aspirin and heparin.

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Patient Education

Patient education may include the following:

• Stress the importance of early recognition of a possible clinical event.
• Instruct patients taking warfarin to avoid sports with excessive contact.
• Instruct patients taking warfarin to avoid excessive consumption of foods that contain vitamin K.^[45]
• Limit activity in patients with acute deep venous thrombosis (DVT).
• Instruct the patient to avoid prolonged immobilization.
• Discuss the importance of planned pregnancies so that long-term warfarin can be switched to aspirin and heparin before pregnancy is attempted.
• Stress the importance of minimizing modifiable risk factors in primary prevention of aPL-positive patients with no history of thrombosis.

For patient education information, see Blood Clot in the Legs.

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