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Management of antiphospholipid syndrome

Management of antiphospholipid syndrome
Literature review current through: Sep 2023.
This topic last updated: Nov 08, 2022.

INTRODUCTION — Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by venous or arterial thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL) that persist over time. APS can occur as a primary condition, or it can occur in the presence of systemic lupus erythematosus (SLE) or another systemic autoimmune disease.

This topic reviews major management decisions in APS, including choice of anticoagulant, duration of anticoagulation, and other treatment considerations.

Separate topic reviews discuss the pathogenesis, clinical manifestations, and diagnosis of APS, as well as the management of APS during pregnancy and the diagnosis and management of catastrophic APS (CAPS):

Pathogenesis (see "Pathogenesis of antiphospholipid syndrome")

Clinical manifestations (see "Clinical manifestations of antiphospholipid syndrome")

Diagnosis (see "Diagnosis of antiphospholipid syndrome")

Effects on the kidney (see "Antiphospholipid syndrome and the kidney")

Management in pregnancy (see "Antiphospholipid syndrome: Obstetric implications and management in pregnancy")

CAPS (see "Catastrophic antiphospholipid syndrome (CAPS)")

TERMINOLOGY

Antiphospholipid syndrome – Antiphospholipid syndrome (APS) describes a clinical autoimmune syndrome characterized by venous or arterial thrombosis and/or pregnancy morbidity in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPL) [1].

APS can occur as a primary condition or in the setting of systemic lupus erythematosus (SLE) or another systemic autoimmune disease.

APS can be further classified according to the type of clinical manifestation: thrombotic or obstetric. In some cases, both may be present. In catastrophic APS (CAPS), life-threatening multiorgan involvement is present.

Thrombotic APS – Thrombotic APS is used to describe patients diagnosed with APS based on venous or arterial thrombosis and persistent laboratory criteria for aPL.

Obstetric APS – Obstetric APS is used to describe patients diagnosed with APS based on an APS-defining pregnancy morbidity (including fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, or multiple embryonic losses [before 10 weeks gestation]) and persistent laboratory criteria for aPL.

Individuals with both an APS-defining pregnancy morbidity and thromboembolic complications are referred to as having both thrombotic and obstetric APS.

CAPS – Catastrophic APS (CAPS) is a rare, life-threatening form of APS characterized by thrombotic complications, including both macrovascular and microvascular, affecting multiple organs that develop simultaneously or over a short period of time. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Definitions'.)

Antiphospholipid antibodies – aPL are a laboratory finding of APS. When persistent (≥12 weeks), these antibodies are a component of the clinical syndrome of APS. They can also be seen as a transient finding following infection or other acute illness.

The aPL most important for diagnosing APS are (see "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'):

Anticardiolipin (aCL)

Anti-beta2 glycoprotein I (anti-beta2GPI)

Lupus anticoagulant (LA)

Antithrombotic therapy may include:

Antiplatelet agents – Antiplatelet agents (typically aspirin) are generally thought to be useful in preventing arterial events.

Anticoagulants – Anticoagulation is typically used as secondary prevention for venous or arterial thrombosis or as prophylaxis in high-risk settings.

PRIMARY THROMBOSIS PREVENTION — Primary prevention refers to antithrombotic therapy used in individuals with obstetric antiphospholipid syndrome (APS) or isolated antiphospholipid antibodies (aPL) who have not had an APS-related thrombosis.

The question of primary thrombosis prevention is raised when a patient is found to have positive aPL on testing that has been done for reasons other than as part of an acute thrombosis workup. Examples in which the presence of aPL may be identified for reasons other than thrombosis include:

Evaluation for systemic lupus erythematosus (SLE)

Recurrent pregnancy loss

Livedo reticularis (picture 1) or racemosa (picture 2)

Unexplained prolonged activated partial thromboplastin time (aPTT)

Unexplained thrombocytopenia

Positive screening test for syphilis

Risk of a first thrombosis with aPL — The presence of antiphospholipid antibodies (aPL) alone appears to be associated with a small increased risk of thrombosis in some individuals. Data on which populations are at increased risk and the magnitude of the risk are limited and are based on observational studies. The following appear to be risk factors for a first thrombosis in individuals with aPL:

Systemic rheumatic disease, particularly SLE

A "high-risk" aPL profile (defined as a persistent lupus anticoagulant [LA], double positive aPL [any combination of LA, anticardiolipin (aCL) antibodies, or anti-beta2 glycoprotein I (anti-beta2GPI antibodies)], or triple positive aPL [all three aPL tests], or persistently high aPL titers)

History of obstetric APS

Additional risk factors for venous thromboembolism (VTE; eg, recent major surgery, estrogen use, inherited thrombophilia) or arterial thromboembolism (eg, hyperlipidemia, tobacco use)

Although SLE is associated with an increased risk of arterial and venous thromboembolic events independent of aPL, findings from observational studies suggest that this risk may be further increased in the presence of aPL [2-5]. A review of observational studies estimated an annual risk of thrombosis among aPL-positive individuals, including those with a systemic rheumatic disease, of <5.3 percent; the annual risk of among aPL-positive individuals without a systemic rheumatic disease was estimated at <1 percent [6,7].

Several studies have suggested that SLE with a high-risk aPL profile is associated with increased risk of future thromboembolic events [3-5]. As examples:

A meta-analysis including 2248 patients with SLE found that patients with LA had a sixfold increased risk of VTE (odds ratio [OR] 5.61, 95% CI 3.80-8.27) compared with patients without LA, and those with aCL had a twofold increased risk (OR 2.17, 95% CI 1.51-3.11) [4]. However, the analysis did not account for other risk factors that could contribute to VTE risk.

A cohort study of 119 patients with aPL, more than half of whom had a systemic rheumatic disease (mostly SLE), found that the presence of double or triple positive tests for aPL was a risk factor for future thrombotic events, whereas a single positive test for aPL was not [5]. The annual rate of first thrombotic events in individuals with any single positive aPL was 0.65 percent (which is similar to the baseline risk in a healthy population), compared with 1.27 percent in patients who were double or triple positive for aPL.

Studies evaluating the risk of thrombosis associated with a high-risk aPL profile in individuals without an autoimmune disease have shown mixed results, with some studies suggesting no increased risk during the follow-up period [8], and others demonstrating an increased risk [9,10]. In one study that evaluated thrombosis risk in 179 individuals without SLE who had an isolated, persistently positive LA and were followed for approximately three years, seven individuals had thromboembolic events (1.3 percent per person-year) [9]. All seven individuals who had an event had at least one additional major risk factor for thromboembolism, suggesting a minor, if any, contribution of aPL as a risk factor for thrombosis. In another study including 104 patients with a triple positive aPL profile who were followed for a mean of 4.5 years, the cumulative incidence of first thromboembolic event after 10 years was 37 percent (95% CI 19.9-54.3 percent) [10].

Several, but not all, studies have reported an increased risk of thrombotic events in individuals with obstetric APS who have not had a prior thrombosis [11-15]. As examples:

In a prospective observational study including 1592 individuals with a history of pregnancy loss that fulfilled obstetric criteria for APS but who had not had a prior thrombotic event, those individuals who tested positive for aPL were more likely to have a thrombotic event compared with those who tested negative for aPL [14]. Results were independent of whether an inherited thrombophilia variant was present. The higher rate of thrombotic events in those with aPL was observed despite the use of low-dose aspirin prophylaxis in all groups.

In a smaller retrospective study of 115 individuals with obstetric APS, 12 (10.4 percent) developed thrombotic events over a mean follow-up time of 10.91±4.47 years [15]. Most of them had an arterial thrombosis, three with stroke and six with a transient ischemic attack (TIA). An important limitation of the study was that other risk factors for thrombosis were not included in the analysis.

By contrast, a retrospective case-control study comparing 141 individuals with unexplained recurrent pregnancy loss matched with 141 individuals with aPL-associated pregnancy loss did not report a statistically significant difference in the incidence of thrombotic events during the median follow-up period of 7.3 years [12].

Limited role of antithrombotic therapy for primary prevention

Our approach — For patients who have aPL but have not had a thrombosis or an APS-defining pregnancy morbidity, we suggest not routinely using antithrombotic therapy (aspirin or anticoagulation) for primary thrombosis prevention. This suggestion applies to individuals with SLE and individuals with APS based on obstetric criteria alone.

However, some individuals may reasonably choose to take aspirin for primary thrombosis prevention, especially if they would derive other benefits such as colorectal cancer risk reduction and they are willing to accept the slightly increased risk of bleeding. The decision about whether to use aspirin or anticoagulation in aPL-positive individuals without APS during pregnancy is discussed separately. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy", section on 'Management'.)

This approach is based on a relatively low baseline risk of thrombosis in these individuals, low-quality evidence that either anticoagulation or aspirin appreciably reduces this risk, and a known increase in bleeding with either anticoagulation or antiplatelet therapy, although the absolute increase in bleeding risk with aspirin is very small. (See 'Evidence for primary thrombosis prevention' below.)

Our approach differs somewhat from that of the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) guidelines, which suggest low-dose aspirin for primary prophylaxis in patients with a high-risk aPL profile (defined as a finding on two or more occasions at least 12 weeks apart of an LA, double or triple aPL positivity, or persistently high aPL titers, in an individual with or without SLE) [16]. Per these guidelines, low-dose aspirin can also be considered for those individuals with a low-risk aPL profile (ie, isolated aCL antibodies or anti-beta2GPI antibodies at low to medium titers or transiently positive aPL). The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends suggests that the use of low-dose aspirin for primary prevention should be individualized [17].

The risk of bleeding from low-dose aspirin is smaller than that with anticoagulation; generally, aspirin is estimated to increase bleeding risk approximately 50 percent (1.5 times) over the individual's baseline risk, with a relatively small absolute increase in the majority of otherwise healthy individuals (range 4 to 18 additional extracranial bleeds per 1000 individuals over a 10-year period, depending on baseline risk). Additional information on the potential benefits and risks of bleeding with aspirin is provided in separate topic reviews. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding' and "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

Evidence for primary thrombosis prevention — The evidence for primary thrombosis prevention in individuals with aPL is mixed, with limited data suggesting a possible benefit from aspirin:

A 2018 Cochrane review that included 9 randomized trials involving 1044 participants with positive aPL who had not had a thrombotic event concluded that there was insufficient evidence to demonstrate benefit or harm of using aspirin or aspirin plus an anticoagulant in these individuals [18]. However, the number of events in the trials analyzed was low overall, making the data challenging to interpret. All of the trials included were at high or unclear risk of bias. Furthermore, most of the trials compared combinations of different therapies, with only one trial (the Antiphospholipid Antibody Acetylsalicylic Acid [APLASA] study) comparing aspirin alone with placebo [19].

The APLASA trial is the only randomized trial to compare aspirin versus placebo in individuals with persistently positive aPL but no history of thrombosis or pregnancy morbidity; in this trial, 98 individuals (approximately two-thirds with SLE) were randomly assigned to receive aspirin (81 mg daily) or placebo for a mean of 2.3 years [19]. Three patients in the aspirin group developed thrombosis (two venous and one arterial), compared with none in the placebo group, a difference that was not statistically significant (hazard ratio [HR] 1.04, 95% CI 0.69-1.56).

A 2014 meta-analysis consisting mostly of observational studies that included 1208 individuals with aPL (some had SLE and some did not) found that individuals taking low-dose aspirin had a lower rate of thrombosis (OR for first venous or arterial thrombosis 0.50, 95% CI 0.27-0.93) [20]. There was significant heterogeneity across studies. One subgroup analysis demonstrated that low-dose aspirin was protective against arterial but not venous thrombosis, and another subgroup analysis found aspirin was only associated with a statistically significant reduction in thrombosis in retrospective (but not prospective) studies.

There is also limited evidence suggesting a protective effect of aspirin for primary thrombosis prevention among individuals with obstetric APS. A subgroup analysis from the 2014 meta-analysis discussed above limited to females without SLE who had a history of obstetric APS found that low-dose aspirin was associated with a lower rate of thrombosis (pooled OR 0.25, 95% CI 0.10-0.62) [20]. A retrospective analysis of 65 individuals with obstetric APS followed for a mean of eight years found a lower thrombosis rate in those who took aspirin (10 versus 59 percent in individuals who did not take aspirin) [21]. However, a prospective observational study with 1592 individuals with consecutive spontaneous abortions, none of whom had a prior thrombotic event, found a higher rate of thrombotic events in the group with aPL compared with those without aPL, despite the use of low-dose aspirin prophylaxis in all [14].

A follow-up 2015 meta-analysis of observational studies involving 497 individuals with an isolated positive aPL found a reduced risk of thromboembolism among patients who were treated with low-dose aspirin compared with those not treated with aspirin (adjusted HR 0.43, 95% CI 0.25-0.75) [22]. A subgroup analysis showed a protective effect of aspirin against arterial thrombosis (HR 0.43, 95% CI 0.20-0.93) but not venous thrombosis (HR 0.49, 95% CI 0.22-1.11). The analysis excluded several important studies.

The role of anticoagulation with warfarin in primary thrombosis prevention was evaluated in a 2014 trial that randomly assigned 166 aPL-positive patients to receive either low-dose aspirin or low-dose aspirin plus low-intensity warfarin (target international normalized ratio [INR] 1.5; range 1.3 to 1.7) for approximately three years [23]. Approximately three-fourths of the patients had SLE, and one-fourth had obstetric morbidity. There were four thromboembolic events in each group (5 percent; 1.8 percent per person-year), demonstrating that addition of low-intensity warfarin to aspirin did not confer significant thrombotic risk reduction. However, this study did not address the benefit of standard-dose warfarin.

INITIAL MANAGEMENT OF ACUTE THROMBOSIS

Approach to anticoagulation — Most patients who present with a thrombotic event and suspected antiphospholipid syndrome (APS) have not had prior testing for antiphospholipid antibodies (aPL). Furthermore, confirmatory testing of aPL must be performed at least 12 weeks after the initial testing. Thus, the initial choice of anticoagulant is largely based on clinical suspicion for APS in the setting of a new venous or arterial thrombotic event. The diagnosis of APS and the role of testing for aPL, including testing for aPL while the patient is receiving an anticoagulant, are discussed separately. (See "Diagnosis of antiphospholipid syndrome", section on 'When to suspect the diagnosis' and "Diagnosis of antiphospholipid syndrome", section on 'Diagnostic evaluation'.)

In individuals with suspected APS, warfarin is typically preferred over a direct oral anticoagulant (DOAC), although a DOAC may reasonably be used in selected individuals. We generally individualize these decisions based on the clinical likelihood of APS versus a patient with a thrombosis and transiently elevated aPL. The data and rationale regarding long-term anticoagulant choice are discussed below. (See 'Long-term anticoagulation' below.)

In patients with acute thrombosis but no previous aPL testing, each of the following findings increases the likelihood of APS and would favor use of warfarin (preceded by low molecular weight heparin [LMWH]) rather than a DOAC:

High-risk aPL profile – High-risk profile includes the presence of lupus anticoagulant (LA) [9], or double positive aPL (any combination of LA, anticardiolipin [aCL] antibodies, or anti-beta2 glycoprotein I [anti-beta2GPI] antibodies), or triple positive aPL (all three aPL tests) [24], especially with high aCL/anti-beta2GPI titers.

Arterial thrombosis (rather than venous), particularly among younger patients.

Systemic rheumatic disease, especially systemic lupus erythematosus (SLE).

Prior history of obstetric APS or pregnancy morbidity concerning for APS.

The following scenarios suggest a lower likelihood of APS and would reduce concerns about the use of a DOAC:

An acute illness such as a viral infection, which can cause transient aPL positivity.

An obvious provoking factor for venous thromboembolism (VTE) such as recent surgery (in the absence of other features suspicious for APS).

Traditional cardiovascular risk factors in an individual with arterial thrombosis.

Administration of heparin and warfarin, adverse effects, and treatment of bleeding are presented separately. (See "Heparin and LMW heparin: Dosing and adverse effects" and "Warfarin and other VKAs: Dosing and adverse effects" and "Biology of warfarin and modulators of INR control" and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding' and "Management of warfarin-associated bleeding or supratherapeutic INR".)

Additional information about the dosing and administration of DOACs is presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Separate topic reviews provide additional details of management regarding the initial stabilization and management of venous and arterial thromboembolic events, which are similar to management in individuals without APS, with the exception of preferring warfarin over a DOAC:

Pulmonary embolism (see "Overview of acute pulmonary embolism in adults" and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration")

Deep vein thrombosis (DVT) (see "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)")

Stroke (see "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack")

Myocardial infarction (see "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction")

Other sites (see "Central and branch retinal artery occlusion" and "Renal infarction" and "Acute mesenteric arterial occlusion")

Importance of baseline coagulation testing — Baseline testing of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be performed in all individuals with thromboembolism. This testing is particularly important in individuals with APS because aPL can artificially prolong these clotting times (the LA phenomenon). The aPTT is more likely to be artificially prolonged, but both tests can be abnormal. The prolongation of the clotting times is a laboratory artifact and does not reflect any degree of anticoagulation. (See "Clinical use of coagulation tests", section on 'Causes of prolonged PT' and "Clinical use of coagulation tests", section on 'Causes of prolonged aPTT'.)

If the baseline PT and/or aPTT are prolonged, they cannot be used to adequately assess anticoagulation, and it is necessary to use an alternative assay that is insensitive to the aPL (eg, anti-factor Xa activity for heparin, alternative thromboplastin reagent for warfarin). (See 'Anticoagulant monitoring' below.)

SECONDARY THROMBOSIS PREVENTION — Secondary thrombosis prevention refers to the period after the initial three to six months of treatment for the acute thrombotic event. By this time, patients should have had confirmatory antiphospholipid antibody (aPL) testing to demonstrate the persistence of aPL. (See "Diagnosis of antiphospholipid syndrome", section on 'Timing of testing'.)

Long-term anticoagulation — For most nonpregnant individuals with antiphospholipid syndrome (APS), we suggest anticoagulation with warfarin rather than a direct oral anticoagulant (DOAC). This is especially true for individuals who have had an arterial thrombosis.

Evidence suggests that DOACs are less effective than warfarin for recurrent thrombosis prevention in patients with APS [25-31], especially in those with a history of arterial events. However, the use of DOACs may be reasonable in a few selected cases of APS, particularly among those who have features of lower-risk disease (single venous thrombosis and low-risk aPL profile) or those who cannot tolerate warfarin. A low-risk aPL profile is defined as isolated anticardiolipin (aCL) or anti-beta2 glycoprotein I (anti-beta2GPI) at low to medium titer [16]. In these settings, it is important to inform the patient about the available evidence and possible reduced benefit of a DOAC relative to warfarin.

Data supporting the increased risk of recurrent thrombosis associated with the use of a DOAC compared with warfarin include the following:

The largest trial to compare warfarin with a DOAC for secondary thrombosis prevention randomly assigned 190 patients with APS and venous or arterial thrombosis to receive warfarin or rivaroxaban over a three-year period [31]. Rivaroxaban did not meet the prespecified noninferiority margin of 1.40. There were more recurrent thromboses in the rivaroxaban group (6.3 percent of warfarin-treated patients versus 11.6 percent of rivaroxaban-treated patients; relative risk [RR] 1.83; 95% CI 0.71-4.76), and recurrent thrombotic events in the rivaroxaban group were predominantly arterial, with recurrent stroke occurring in 10 percent of patients receiving rivaroxaban versus none of those receiving warfarin. Major bleeding events were similar between the two groups.

A 2018 trial that randomly assigned 120 patients with thrombotic APS and triple aPL positivity to receive warfarin or rivaroxaban was stopped early at 1.5 years due to an increased rate of the composite outcome of thromboembolic events, major bleeding, and vascular death in the rivaroxaban arm (3 percent with warfarin versus 19 percent with rivaroxaban) [27]. Thromboembolic events occurred in 12 percent of patients in the rivaroxaban group (four ischemic strokes and three myocardial infarctions) compared with none in the warfarin group. There were also more major bleeding events in the rivaroxaban group (7 versus 3 percent).

In a 2016 trial, 110 patients with APS and a history of venous thromboembolism (VTE) only who had been taking warfarin for at least three months were randomly assigned to continue warfarin (target international normalized ratio [INR] 2.5) or switch to rivaroxaban for six months [25]. No thrombotic events were observed in either group during the six-month follow-up. The primary outcome of this trial was endogenous thrombin potential (a laboratory marker of thrombin generation), which was inferior for rivaroxaban compared with warfarin. In addition, the duration of follow-up was short, the trial excluded individuals with a history of arterial events or recurrent thrombosis, and the proportion of participants with a high-risk antibody profile (ie, triple positivity) was low at only 28 percent.

In a 2022 open-label trial (closed to enrollment in 2019) that included 48 patients with thrombotic APS (approximately one-third with arterial thrombosis) who were randomly assigned to receive apixaban or warfarin, stroke occurred in 6 of 23 patients of the apixaban arm compared with 0 of 25 of the warfarin arm during the 12-month follow-up period [32]. There was one major bleeding event in the warfarin group and none in the apixaban group. Apixaban dosing was increased approximately halfway through the trial, from 2.5 mg twice daily (the dose for primary VTE prophylaxis) to 5 mg twice daily (the dose for atrial fibrillation and VTE treatment). Other limitations included early termination, low patient accrual, and multiple protocol modifications.

A systematic review from 2016 that included 122 case reports of patients with APS treated with a DOAC identified 19 patients who experienced a recurrent thrombosis during DOAC therapy [26]. Triple positivity for aPL was associated with a 3.5-fold increased risk of recurrent thrombosis. Additional observational studies have also documented relatively higher rates of recurrent thrombosis in individuals treated with DOACs, especially those with triple aPL positivity and/or previous arterial thrombosis [26,29,33].

Venous thrombosis — For patients with VTE, we suggest anticoagulation with warfarin with a target INR of 2.5 (range 2 to 3) rather than a higher INR range, such as 3 to 4. Our approach is generally consistent with guidelines [34-36]. Individuals who are pregnant or who become pregnant are treated with low molecular weight heparin (LMWH). (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy", section on 'Management of APS during pregnancy' and 'Management during pregnancy' below.)

Evidence to support standard-intensity warfarin with a target INR range of 2 to 3 rather than a higher INR range in individuals with APS and VTE comes from two randomized trials and additional observational studies presented below. The studies showed low overall rates of recurrent thrombosis that did not appear to be lower in patients who received warfarin with the higher target INR range:

In a trial from 2003, 114 patients with aPL and a previous VTE or arterial thrombosis were randomly assigned to receive standard-intensity warfarin (INR 2 to 3) or high-intensity warfarin (INR 3.1 to 4) and were followed for 2.7 years [37]. The difference in the rate of recurrent thrombosis was not statistically significant and showed a trend towards a greater thrombosis risk with high-intensity therapy (3.4 percent with standard intensity versus 10.7 percent with high intensity; hazard ratio [HR] for high-intensity warfarin group 3.1, 95% CI 0.6-15). Bleeding episodes occurred at similar rates in both groups (2.2 and 3.6 percent per year for the moderate- and high-intensity treatment groups, respectively).

In a trial from 2005, 109 patients with APS and previous VTE or arterial thromboses were randomly assigned to receive warfarin at standard-intensity (INR 2 to 3) or high-intensity (INR 3 to 4.5) for 3.6 years [38]. The rates of recurrent thrombosis were not statistically different between the groups (5.5 for standard intensity and 11.1 percent for high intensity; HR for high-intensity warfarin group 1.97, 95% CI 0.49-7.89). There was a trend towards more bleeding episodes in patients receiving high-intensity therapy compared with standard-intensity warfarin (27.8 versus 14.6 percent, respectively; HR 2.18, 95% CI 0.92-5.15).

A retrospective study including 66 individuals with APS (half of whom also had systemic lupus erythematosus [SLE]) treated with warfarin to a target INR of 3.5 (INR range 3 to 4) for approximately five years found an annualized bleeding rate of 6 percent per 100 patient-years (95% CI 1.6-15.0) [39]. There were four major bleeding events, none of which were fatal. The rate of intracranial bleeding was 1.5 percent per 100 patient-years (95% CI 0.4-8.4). These bleeding rates are similar to or slightly greater than those seen in anticoagulant trials or in other anticoagulant-treated populations. Despite the relatively intensive anticoagulation target, six patients had recurrent thrombotic events (9 percent per 100 patient-years).

General discussions of risk factors for bleeding with anticoagulation and factors that affect INR control are presented separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Biology of warfarin and modulators of INR control", section on 'Overview of INR control'.)

Additional information about the dosing and administration of DOACs is presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Arterial thrombosis — The optimal management of patients with APS who have had an arterial event (ischemic stroke or myocardial infarction) is less clear, and consensus among experts is lacking [34,40]. Options include standard-intensity warfarin (INR range 2 to 3), standard-intensity warfarin plus low-dose aspirin, and higher-intensity warfarin (INR >3). Individuals with prior arterial thrombosis have a high risk of recurrent arterial thrombosis if treated with a DOAC rather than warfarin. (See 'Long-term anticoagulation' above.)

For most patients with arterial thrombosis, we suggest standard-intensity warfarin (INR range 2 to 3) plus low-dose aspirin rather than a higher INR range and/or either therapy alone. If present, other cardiovascular risk factors such as hypertension, hyperlipidemia, and smoking should also be addressed. Some patients with arterial thrombosis who do not have other cardiovascular risk factors, however, may reasonably be treated with standard-intensity warfarin alone.

Guidelines from the 13th and 16th International Congress on Antiphospholipid Antibodies included recommendations that patients with APS and an arterial thrombosis receive either low-dose aspirin plus standard-intensity warfarin (INR range 2 to 3) or warfarin at an INR >3 [17,34]. However, several experts believe that standard-intensity warfarin is equally effective in this setting. The guidelines by the European Alliance of Associations for Rheumatology (EULAR) include all of these options for secondary prevention of arterial thrombosis, with the caveat that the individual patient's risk of bleeding and recurrent thrombosis needs to be taken into consideration [16].

There are limited data to help guide the optimal approach of anticoagulation in patients with APS who have had an arterial event:

Data to support standard-intensity anticoagulation with warfarin are described above in the randomized trials (see 'Venous thrombosis' above), in which almost 25 percent of the thromboses in each of the studies were arterial [37,38]. However, limited conclusions can be drawn given the small number of patients with arterial events.

A systematic review of mostly retrospective studies observed a dose effect of anticoagulation, with fewer recurrent thrombotic events at an INR >3 (3.8 percent; 4 arterial and 1 venous) compared with an INR <3 (23 percent; 13 arterial and 16 venous) [41]. These findings favor a higher INR for patients with arterial events; however, the efficacy of a higher INR has never been evaluated in a randomized trial.

A trial that randomly assigned 20 individuals with APS and ischemic stroke to receive aspirin alone (100 mg) or aspirin plus warfarin (INR 2 to 3) found a higher cumulative incidence of recurrent stroke in the aspirin-alone group at a mean follow-up of approximately four years [42]. However, this trial did not include a warfarin-alone arm. The number and type of events in each group were not specified.

A small retrospective study involving 90 patients with APS and a history of arterial thrombosis evaluated the role of dual antiplatelet therapy (DAPT) versus other approaches (a single antiplatelet agent, warfarin alone, or warfarin plus an antiplatelet agent) and reported a lower rate of recurrent arterial or venous thrombosis with DAPT [43]. However, the number of individuals in each group was too small to allow meaningful conclusions or to influence practice.

Anticoagulant monitoring — Accurate assessment of anticoagulation intensity is important for the management of APS [44]. For individuals with a normal baseline activated partial thromboplastin time (aPTT) who are treated with unfractionated heparin, the aPTT can be used for monitoring. For individuals with a normal baseline prothrombin time (PT)/INR, warfarin can be monitored by standard INR measurements. Routine monitoring of warfarin therapy is usually done in an anticoagulation clinic or with a combination of self-monitoring or self-management. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'INR-based initial dose adjustment' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Establishing a maintenance dose'.)

Challenges in PT/INR monitoring – Some individuals may have abnormal baseline PT; these individuals must be monitored using an assay other than the standard PT and INR, as listed below. Although prolongation of the baseline PT is much less common than prolongation of the baseline aPTT in individuals with APS, prolongation of the baseline PT may occur in approximately 5 to 10 percent due to a lupus anticoagulant (LA) effect [45,46].

Baseline prolongation occurs less frequently with the PT assay because most routinely used thromboplastins are insensitive to LA, and higher concentrations of phospholipid are used in the PT assay; these phospholipids titrate out the LA activity [47]. In individuals with a baseline prolongation of the PT/INR, this baseline prolongation should not be interpreted to mean that the patient is anticoagulated, as this prolongation is strictly an in vitro artifact. (See "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR'.)

In individuals with a prolonged baseline PT/INR, there are other options for monitoring warfarin. However, it should be noted that these approaches have limitations that should be discussed with the testing laboratory prior to their use [45,47,48].

An alternative thromboplastin reagent such as one that includes a combination of thromboplastins or one that has been demonstrated to be insensitive to the patient's aPL or LA could be used [45,48,49]. Instrument-specific INR determinations for such a reagent may not be available.

In principle, an assay for factor X that uses a chromogenic substrate (color change) rather than time to form a clot could be used; this is referred to as a chromogenic factor X assay [45,48]. However, such an assay has not been developed and validated for warfarin monitoring, and communication with the testing laboratory should occur if this approach is being considered. Additional information about the chromogenic factor X assay is presented separately. (See "Clinical use of coagulation tests", section on 'Factor X chromogenic assay'.)

Challenges in aPTT monitoring – The aPTT is used to monitor the effect of therapeutic-dose unfractionated heparin; routine monitoring is not required for LMWH unless there are concerns about dosing due to a very high body mass index or chronic kidney disease.

For patients with a prolonged baseline aPTT who require unfractionated heparin, such as in the perioperative setting, heparin can be monitored instead using an anti-factor Xa assay. (See "Clinical use of coagulation tests", section on 'Monitoring heparins'.)

Duration of anticoagulation — For most individuals with APS and an unprovoked thrombotic event, we recommend lifelong anticoagulation. This is based on the high likelihood of recurrence without anticoagulation and the potentially devastating nature of recurrent thromboembolic events, especially arterial events.

However, stopping anticoagulation in selected APS patients with a clearly provoked thrombosis, especially in the setting of low titer aPL, can be considered after discussing the risks and benefits with the patient. In patients with a persistently positive LA test performed off anticoagulation and/or moderate to high titer aCL/anti-beta2GPI, aPL usually do not disappear during long-term follow-up. Thus, aPL should be repeated if there is a consideration to stop anticoagulation; however, the results of repeat testing should not be the only determinant of the decision.

Evidence from retrospective series shows a high rate of recurrent thromboembolism in individuals with APS who stopped anticoagulation, with estimates of approximately 50 to 70 percent, or 30 percent per year [50-52]. However, there is also evidence suggesting that the actual risk of recurrent thrombosis in patients with APS who have received an initial course of anticoagulation may not be as high as previously thought. A systematic review to assess recurrence risk after a first VTE (with 3114 patients from 6 randomized trials and 2 cohort studies) found a trend towards an increased risk for VTE recurrence after stopping anticoagulation that did not meet statistical significance [53]. However, the quality of the evidence was low, and two separate measurements of aPL were not performed.

It is likely that non-aPL thrombosis risk factors also contribute to recurrent thrombotic events. A retrospective analysis of 11 patients who had a history of a single vascular event (mostly provoked VTE) found that it was possible to successfully discontinue anticoagulation in selected aPL-positive patients after a mean of 25 months [54]. In 2 small case series involving 10 and 11 patients with APS whose aPL became persistently negative, no thrombosis recurrence was observed after stopping anticoagulation during the one- to two-year follow-up period [55,56]. However, in both series, none of the patients presented with an arterial thrombosis, and most of the patients had an additional reversible risk factor for VTE. In addition, the patients carried only a single positive aPL, suggesting that they had a lower-risk aPL profile, and the duration of follow-up was short.

Limited role of alternative agents — Alternative anticoagulants or adjunctive therapeutic options have been studied, but the available evidence does not support their routine use.

Other anticoagulants – Data regarding DOACs are discussed above (see 'Long-term anticoagulation' above). Only one case report described experience with fondaparinux in a patient with APS who did not have a stable therapeutic INR with warfarin and subsequently developed suspected heparin-induced thrombocytopenia (HIT) in the setting of LMWH [57]. During the subsequent 18 months, the patient did not have a thromboembolic event while on fondaparinux. More data are needed before use of fondaparinux can be considered as an alternative to LMWH or warfarin.

Immunomodulatory agents – APS is an autoimmune disorder; the role of immunomodulatory agents for the treatment of APS has thus been proposed [58]. However, there is a lack of high-quality data to guide practice, and there is no good-quality evidence to guide selection of a specific immunomodulatory agent. We often add hydroxychloroquine (HCQ) and statins for patients with recurrent thrombosis despite adequate anticoagulation, and we often use rituximab for patients with hematologic manifestations of APS (eg, thrombocytopenia) or a thrombotic microangiopathy (TMA). (See 'Thrombocytopenia' below.)

RituximabRituximab can be used in aPL-positive patients with hematologic manifestations or a TMA (along with other therapies for a primary TMA as indicated) [59]; however, there are insufficient data to recommend routine use of rituximab in thrombotic APS. Rituximab is often used in other systemic rheumatic diseases, with studies suggesting that rituximab reduces antibody titers in several antibody-mediated autoimmune diseases. Case reports have supported the use of rituximab in challenging cases of APS [60-62]. In addition, a pilot open-label phase 2 trial for the treatment of noncriteria manifestations of APS (thrombocytopenia, skin ulcers, and cognitive dysfunction) included 19 patients and found that rituximab was well tolerated and effective in some patients; rituximab had no effect on aPL levels in this study [63]. (See 'Organ system-specific manifestations' below.)

Hydroxychloroquine – HCQ can be used as an additional treatment in difficult-to-treat APS. HCQ is used routinely in the treatment of SLE, but data are insufficient to recommend its use in the setting of APS or aPL without SLE. In individuals with SLE and APS, HCQ appears to reduce the incidence of thrombotic complications, but it is not clear whether the reduction is due to treatment of the SLE or the APS [2,6,64].

Statins – Statins can be used as an additional treatment in difficult-to-treat APS. Limited data suggest that statins may have a beneficial effect for patients with APS by reducing proinflammatory and prothrombotic markers [65-67]. However, there are insufficient data to recommend the routine use of statins in patients with APS in the absence of hyperlipidemia.

EculizumabEculizumab has been used in refractory APS [68]. Use in catastrophic APS (CAPS) is discussed separately. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Eculizumab'.)

Recurrent thromboembolism despite adequate anticoagulation — Recurrent thromboembolism despite adequate anticoagulation is relatively rare, and often there are unique circumstances that must be considered. There are several possible interventions, and the choice among them is individualized.

It is important to determine that the patient was therapeutically anticoagulated with warfarin at the time of the event. It is also important to evaluate for other possible reversible thrombosis risk factors and address these if present. (See 'Anticoagulant monitoring' above.)

If the recurrent thrombosis occurred despite a documented adequate INR (range 2 to 3) and without an additional major thrombosis risk factor (eg, recent surgery, immobility, estrogen use), one approach is to increase the target INR (eg, range 3 to 4). This approach may be more appropriate for an individual who had a recurrent event when the INR was in the lower end of the target range at the time of the event (eg, INR of 2.1). However, there are no data from randomized trials that support the use of higher-intensity warfarin. (See 'Venous thrombosis' above.)

An alternative approach is switching from warfarin to LMWH. This approach may be more appropriate for an individual who had a recurrent event when the INR was in the higher end of the target range at the time of the event (eg, INR of 2.9). This approach is largely based on our experience and data from a small series that showed successful use of LMWH after initial warfarin failure [69]. (See "Heparin and LMW heparin: Dosing and adverse effects".)

In addition to changes in anticoagulation (increasing the target INR or switching to LMWH), some experts may add another medication, such as low-dose aspirin, HCQ, and/or a statin, as discussed above. (See 'Limited role of alternative agents' above.)

OTHER TREATMENT CONSIDERATIONS

Routine follow-up — Individuals with no other systemic autoimmune diseases who are otherwise tolerating anticoagulation are generally seen as an outpatient once or twice a year.

Routine laboratory monitoring is limited to coagulation studies (performed prior to initiating anticoagulation and during therapy to guide dosing), a complete blood count (CBC), and a metabolic panel to assess kidney function. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Outpatient management'.)

After the confirmation of persistent antiphospholipid antibody (aPL) positivity during the initial diagnosis of antiphospholipid syndrome (APS), repeat aPL testing is generally not indicated unless it will help with future treatment decisions. (See 'Duration of anticoagulation' above.)

Patients who are symptomatic from organ-system involvement (eg, cardiac symptoms, kidney disease) should undergo appropriate evaluations based on their symptoms. (See 'Organ system-specific manifestations' below.)

Reduction of risk factors — In addition to antithrombotic therapy, attention should be paid to minimizing modifiable risk factors for recurrent thrombosis. During the perioperative period, risk reduction may include minimizing the period when anticoagulation is interrupted, initiating early ambulation, and other measures to reduce venous stasis. (See "Perioperative management of patients receiving anticoagulants".)

Estrogen-containing medications should generally be avoided when possible in individuals with APS. (See "Contraception: Counseling for women with inherited thrombophilias", section on 'Personal history of venous thrombosis'.)

Management during pregnancy — Warfarin is not used during pregnancy (especially the first trimester) due to the risks of teratogenicity. Any individual with APS who becomes pregnant is treated with low molecular weight heparin (LMWH) instead of warfarin, as discussed separately. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Use of anticoagulants during pregnancy and postpartum".)

ORGAN SYSTEM-SPECIFIC MANIFESTATIONS — Aside from thrombosis, other "noncriteria" manifestations of antiphospholipid syndrome (APS) may require additional management.

Noncriteria manifestations refer to clinical manifestations of APS that are not part of the revised Sapporo classification criteria (table 1). These manifestations include cardiac valve disease, central nervous system involvement, kidney disease, hemolytic anemia, and thrombocytopenia. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Clinical manifestations'.)

Cardiac disease — Cardiac valvulopathy due to nonbacterial thrombotic endocardial deposits (NBTE) can cause systemic embolic complications. We typically do not screen patients with APS for cardiac valvulopathy by echocardiography unless they are symptomatic (eg, new cardioembolic stroke or heart failure) or a new murmur is appreciated on cardiac examination. (See "Nonbacterial thrombotic endocarditis", section on 'Imaging' and "Nonbacterial thrombotic endocarditis", section on 'Echocardiography'.)

In individuals with APS who have valvular involvement, antiplatelet therapy and warfarin do not appear to cause regression of the valvular lesions, but these therapies may prevent clinical embolic events [70]. In the absence of high-quality data, our approach to managing patients who are antiphospholipid antibody (aPL) positive with valvular disease who have not had a thrombosis is as follows:

The majority of aPL-positive patients with valvular thickening are treated with low-dose aspirin (eg, 81 mg daily), although high-quality data to support this practice are lacking.

In patients at high risk for embolic disease (eg, with vegetations), those who have had systemic embolization, or those who have had a myocardial infarction, anticoagulation should be initiated. Anticoagulation is typically initiated with heparin and transitioned to warfarin (with or without aspirin), with an international normalized ratio (INR) of 2 to 3.

This approach is consistent with a 2003 consensus report on cardiac disease in APS, as well as general guidelines from the American College of Chest Physicians (ACCP) that recommend anticoagulation and control of the underlying disease in individuals who have NBTE and systemic or pulmonary emboli in the absence of APS [71,72]. It seems reasonable to extrapolate this recommendation to individuals with APS, although such individuals were not included in the majority of studies. Additional information regarding the management of NBTE can be found elsewhere. (See "Nonbacterial thrombotic endocarditis".)

There are no clear recommendations for patients who have a thromboembolic event secondary to cardiac vegetations while receiving anticoagulation. In such cases, we would treat these patients in a manner similar to that described above for patients with APS who have a recurrent thromboembolism despite adequate anticoagulation with warfarin (see 'Recurrent thromboembolism despite adequate anticoagulation' above). Surgical consultation may be necessary for those who have thromboembolic complications of NBTE despite anticoagulation.

Central nervous system manifestations — Management of ischemic stroke in patients with thrombotic APS typically involves antithrombotic therapy and other interventions, depending on whether the patient is already receiving anticoagulation. (See "Initial assessment and management of acute stroke" and 'Secondary thrombosis prevention' above.)

In addition to stroke, individuals with APS can develop white matter lesions on magnetic resonance imaging (MRI). These lesions are nonspecific and can also develop in other conditions such as migraine. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Neurologic involvement'.)

For an individual with aPL who has white matter lesions but no clinical suspicion of ischemic stroke, the role of low-dose aspirin is controversial; there are no data for or against aspirin. Decisions of whether to use low-dose aspirin are generally made by evaluating overall cardiovascular risk. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Kidney disease — Complications of APS involving the kidney include aPL-nephropathy, thromboses of arteriovenous grafts in individuals receiving hemodialysis, and thromboses following kidney transplant. Management of these complications is discussed separately. (See "Antiphospholipid syndrome and the kidney".)

Thrombocytopenia — Many individuals with APS have mild thrombocytopenia that does not require treatment. Thrombocytopenia in APS may occur by a number of mechanisms, including direct binding of the aPL to platelet-associated phospholipids, concurrent immune thrombocytopenia (ITP), or other concurrent thrombocytopenic disorder.

A thrombotic microangiopathy (TMA)-like picture can occur in individuals with APS, with severe thrombocytopenia and microangiopathic hemolytic anemia (MAHA), which is inferred from the presence of schistocytes (picture 3) on the peripheral blood smear.

In some cases, these individuals have severe deficiency of the ADAMTS13 protease, consistent with immune thrombotic thrombocytopenic purpura (TTP) [73,74]. It is not clear whether APS increases the risk of immune TTP or if these case reports merely demonstrate the association of two autoimmune conditions in the same patient [75,76]. (See "Diagnosis of immune TTP".)

In other cases, the patient may have catastrophic APS (CAPS), characterized by widespread thrombotic disease with multiorgan failure. (See "Catastrophic antiphospholipid syndrome (CAPS)".)

The two major considerations in individuals with APS and thrombocytopenia are the appropriate treatment for thrombocytopenia and the safety of anticoagulation for thromboembolism in an individual with a low platelet count.

Management of thrombocytopenia – The underlying cause of thrombocytopenia should be investigated because TMAs are treated differently from other causes of thrombocytopenia such as ITP, drug-induced thrombocytopenia, or heparin-induced thrombocytopenia (HIT). The evaluation is described separately. (See "Diagnostic approach to thrombocytopenia in adults".)

ITP is a diagnosis of exclusion and is generally not made in the setting of APS, although individuals with known ITP may develop APS. Immune platelet destruction due to ITP or an ITP-like phenomenon does not always require treatment, especially if the platelet count is >30,000/microL. For patients who do require treatment, therapy typically involves glucocorticoids and/or intravenous immune globulin (IVIG), similar to individuals without APS. The decision to use immunosuppressive therapy, choice and sequence of therapies, and monitoring of response are discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults".)

Possible TMA – For those with evidence of a TMA, the possibility of TTP or drug-induced TMA should be evaluated; therapeutic plasma exchange for a presumptive diagnosis of TTP may be appropriate while awaiting the results of diagnostic testing. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Possible drug-induced thrombocytopenia – For those with a possible drug-induced cause of thrombocytopenia, implicated medications should be discontinued. Testing for drug-dependent antibodies may be appropriate. (See "Drug-induced immune thrombocytopenia".)

Possible HIT – For those with possible HIT, heparin should be discontinued and a non-heparin anticoagulant initiated while awaiting the results of laboratory testing. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Safety of anticoagulation in the setting of thrombocytopenia – All anticoagulants increase bleeding risk, and the decision to use an anticoagulant must balance the potential risks with the potential benefits.

The safety of anticoagulation in individuals with APS and thrombocytopenia has not been well studied, but extrapolation from other populations suggests that anticoagulation is reasonable in individuals with a platelet count >50,000 to 60,000/microL, as long as there is no active, clinically significant bleeding and the platelet count is stable. Anticoagulation may be appropriate in those with lower counts (eg, as low as 30,000/microL), especially if the individual is receiving a therapy that is expected to increase the count [77,78].

For those who require anticoagulation but have more severe thrombocytopenia, interventions to increase the platelet count may be indicated, with the intervention tailored to the specific cause of thrombocytopenia. This subject is discussed in more detail separately. (See "Anticoagulation in individuals with thrombocytopenia".)

Thrombocytopenia does not reduce the risk of thromboembolism in individuals with APS [79,80]. Clinical judgment must be used to weigh the risks and benefits of anticoagulation for each patient, especially for those with lower platelet counts. (See 'Secondary thrombosis prevention' above.)

PROGNOSIS — The prognosis for patients with APS is dependent upon the clinical manifestations that lead to diagnosis. As an example, the prognosis is particularly poor during the initial episode when the patient presents with multisystem disease as seen in catastrophic APS (CAPS). (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Prognosis'.)

One of the longest observational studies on the major causes of morbidity and mortality of APS included 1000 patients who were seen during the period 1999 to 2009 [81]. During the 10-year study period, over 40 percent of patients in the original cohort were lost to follow-up. Morbidity and mortality were as follows:

Recurrent thrombotic or thromboembolic events occurred in 166 patients during the first 5-year period of the study and in 118 patients during the second period, approximately half of whom were taking warfarin. The most common thrombotic events included strokes (5 percent), transient ischemic attacks (TIA; 5 percent), deep vein thrombosis (DVT; 4 percent), and pulmonary embolism (3.5 percent).

Other APS-related manifestations included thrombocytopenia (9 percent), livedo reticularis (8 percent), seizures (3 percent), heart valve thickening or dysfunction (5 percent), microangiopathic hemolytic anemia (MAHA; 4 percent), and skin ulcers (3 percent).

Of the 1000 patients in the study, 127 became pregnant (188 pregnancies) with 73 percent resulting in one or more live births. The most common obstetric complications were early pregnancy loss (17 percent), premature birth (48 percent), and intrauterine growth restriction (26 percent).

Mortality in this cohort was 9.3 percent over 10 years. Causes of death included arterial and venous thromboembolic events (eg, stroke, myocardial infarction, pulmonary embolism, CAPS), bacterial infection, and bleeding.

These data confirm that patients who survive the initial episode remain at risk for recurrent events. Antithrombotic therapy with warfarin or aspirin may reduce the risk of recurrent thromboembolic or obstetrical complications but does not eliminate these risks, which can sometimes be fatal.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antiphospholipid syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Antiphospholipid syndrome (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Primary thrombosis prevention – Antiphospholipid antibodies (aPL) may be associated with a small increased risk of thrombosis, but evidence to support antithrombotic therapy is limited. (See 'Risk of a first thrombosis with aPL' above.)

For patients who have aPL but have not had a thrombosis or an antiphospholipid syndrome (APS)-defining pregnancy morbidity, we suggest not routinely using aspirin or anticoagulation for primary thrombosis prevention (Grade 2C). However, some individuals may reasonably benefit from low-dose aspirin based on general population guidelines or for secondary prevention of cardiovascular disease. The decision about whether to use aspirin or anticoagulants in patients with aPL without APS during pregnancy is discussed separately. (See 'Limited role of antithrombotic therapy for primary prevention' above and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy", section on 'Management'.)

Initial management of acute thrombosis – In individuals with acute thrombosis and suspected APS, warfarin is generally preferred, although a direct oral anticoagulant (DOAC) may reasonably be used in selected cases. We generally individualize these decisions based on the clinical likelihood of APS versus thrombosis and transiently elevated aPL. (See 'Approach to anticoagulation' above.)

Secondary thrombosis prevention – Secondary thrombosis prevention with long-term anticoagulation is the mainstay of therapy for patients with APS due to the high rate of recurrent thrombosis. The main principles of APS management include:

Baseline coagulation testing – All patients should have a baseline prothrombin time (PT) with international normalized ratio (INR) and activated partial thromboplastin time (aPTT) prior to starting anticoagulation. Baseline prolongation of the PT or aPTT is a laboratory artifact and does not indicate auto-anticoagulation. A test that is prolonged at baseline cannot be used to monitor anticoagulation. (See 'Importance of baseline coagulation testing' above and 'Anticoagulant monitoring' above.)

Long-term anticoagulation – For most individuals with APS, we suggest anticoagulation with warfarin rather than a DOAC (Grade 2B). However, a DOAC may be reasonable in selected cases of APS, particularly for patients with lower-risk features such as a single venous thromboembolism (VTE) and single positive aPL test, or those who cannot tolerate warfarin. The individual should be made aware of the available evidence and possible reduced efficacy of DOACs relative to warfarin for APS. (See 'Long-term anticoagulation' above.)

The approach to secondary thrombosis prevention varies depending on whether the thrombosis/thromboembolism is venous or arterial:

-VTE – For individuals with APS and VTE, we suggest anticoagulation with standard-intensity warfarin (INR range 2 to 3) rather than a higher INR range (Grade 2C). (See 'Venous thrombosis' above.)

-Arterial – For most patients with APS and arterial thromboembolism, we suggest anticoagulation with standard-intensity warfarin (INR range 2 to 3) plus aspirin rather than a higher INR range and/or either therapy alone (Grade 2C). Some patients with arterial thrombosis who lack cardiovascular risk factors may reasonably be treated with standard-intensity warfarin alone. (See 'Arterial thrombosis' above.)

Duration of antithrombotic therapy – For most individuals with APS and an unprovoked thrombosis, we recommend lifelong anticoagulation (Grade 1B). This is based on the high likelihood of recurrence without anticoagulation and the potentially devastating nature of recurrent thromboembolic events, especially arterial events. Some individuals with a clearly provoked VTE, especially in the setting of low titer aPL, may consider stopping anticoagulation after three to six months. (See 'Duration of anticoagulation' above.)

Recurrent thromboembolism – Recurrent thromboembolism despite anticoagulation is rare but can occur. If it is confirmed that the individual was therapeutically anticoagulated at the time of the recurrent thrombosis, options include adding aspirin or hydroxychloroquine (HCQ), using a higher INR range, or switching to low molecular weight heparin (LMWH). (See 'Recurrent thromboembolism despite adequate anticoagulation' above.)

Monitoring – Routine laboratory monitoring is limited to coagulation studies (performed prior to initiating anticoagulation and during therapy to guide dosing), complete blood count (CBC), and metabolic panel to assess kidney function; this is typically done every 6 to 12 months. Repeat aPL testing is not performed unless it would alter management. (See 'Other treatment considerations' above.)

Other manifestations – Cardiac vegetations from nonbacterial thrombotic endocardial deposits (NBTE) are generally treated with anticoagulation plus aspirin to reduce embolization risk. Individuals with white matter lesions not due to ischemic stroke may be treated with aspirin. Thrombocytopenia is not a contraindication to anticoagulation in most cases, but the cause should be evaluated in case other therapies are indicated. Kidney manifestations of APS are discussed separately. (See 'Organ system-specific manifestations' above and "Antiphospholipid syndrome and the kidney".)

CAPS – Catastrophic APS (CAPS) is a rare and potentially life-threatening form of APS with widespread thrombosis and organ damage. Management is discussed separately. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Management'.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Bonnie Bermas, MD, Peter Schur, MD, and Andre Kaplan, MD, who contributed to an earlier version of this topic review.

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Topic 4682 Version 51.0

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