Treatment of antiphospholipid syndrome

Authors:
Doruk Erkan, MD, MPH
Thomas L Ortel, MD, PhD
Section Editor:
David S Pisetsky, MD, PhD
Deputy Editors:
Monica Ramirez Curtis, MD, MPH
Jennifer S Tirnauer, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Oct 2018. | This topic last updated: Oct 30,
2018.

INTRODUCTION — Antiphospholipid syndrome (APS) is a systemic autoimmune

disease characterized by venous or arterial thrombosis and/orpregnancy loss in the
presence of persistent expression over time of antiphospholipid antibodies (aPL). APS
can occur as a primary condition, or it can occur in the presence of systemic lupus
erythematosus (SLE) or another systemic autoimmune disease.

The major treatment issues in APS include the treatment of acute thromboembolic
manifestations, the choice of anticoagulation, and the duration of anticoagulation. Other
related issues include the prevention of first thrombosis among patients with aPL who
do not meet criteria for APS. The treatment considerations related to non-obstetric
APS, as well as the management of catastrophic APS (CAPS), will be reviewed here.

Separate topic reviews discuss the pathogenesis, clinical manifestations, and diagnosis
of APS, as well as the management of APS during pregnancy and renal manifestations
of APS, and other associated conditions such as SLE.

●Pathogenesis of APS (see "Pathogenesis of antiphospholipid syndrome")

●Clinical manifestations of APS (see "Clinical manifestations of antiphospholipid

syndrome")

●Diagnosis of APS (see "Diagnosis of antiphospholipid syndrome")

●Pregnancy with APS (see "Antiphospholipid syndrome: Pregnancy implications

and management in pregnant women")

●Renal manifestations of APS (see "Antiphospholipid syndrome and the kidney")

●Clinical manifestations of SLE (see "Overview of the clinical manifestations of

systemic lupus erythematosus in adults")

PRIMARY THROMBOSIS PREVENTION

Risk of thrombosis — The rationale for considering primary thrombosis prevention is
based on the increased risk of thrombosis associated with aPL. However, data are
limited regarding the actual risk of first thromboembolism associated with aPL in
individuals who have not had a thrombosis. Estimates of thrombosis risk in these
individuals are based on a limited number of observational studies, most of which
include patients with systemic lupus erythematosus (SLE) who are already known to
have an increased risk of thrombosis [1-7] (see "Overview of the clinical manifestations
of systemic lupus erythematosus in adults", section on 'Thromboembolic disease'). A
review article suggested that the annual risk of thrombosis among individuals with aPL
in the setting of SLE is likely less than 4 percent, and the risk in individuals with aPL
without SLE is likely less than 1 percent [5].

●Patients without autoimmune disease – One of the few studies to examine the
risk of first thrombosis in aPL-positive individuals without a systemic autoimmune
disease was a prospective observational study including 178 patients [1]. Patients
did not receive thromboprophylaxis except in high-risk settings such as surgery,
and there were no thromboses during the three-year follow-up period. In another
study, the risk of thromboembolism was evaluated in 179 individuals without SLE
who had an isolated but persistently positive lupus anticoagulant (LA) and were
followed for approximately three years [8]. There were seven thromboembolic
events (1.3 percent per person-year). All seven individuals had at least one
additional major risk factor for thromboembolism, suggesting the contribution of
simultaneous risk factors to thrombosis.

●Patients with SLE – Several studies have assessed the risk of first thrombosis
in individuals with SLE and aPL:

•A systematic review and meta-analysis of 2248 patients with SLE found that
patients with LA had an approximately sixfold increased risk for venous
thromboembolism (VTE) compared with those without an LA [9]. SLE
patients with anticardiolipin antibodies (aCL) also had an approximately
twofold increased risk for VTE compared with patients without aCL. However,
the analysis did not account for other risk factors that could also contribute to
the increased risk of a thromboembolic event in such patients.

•In another study, the relationship between VTE and aPL was evaluated in a
prospective cohort of 678 individuals with SLE [4]. The presence of LA
(measured by the Russell viper venom time assay) and aCL antibodies was
assessed quarterly. Multivariate analysis found the presence of LA alone and
in combination with an elevated level of aCL to be associated with an
increased risk of VTE. However, an elevated aCL level alone was not an
independent risk factor for VTE.

•A subsequent cohort study compared 144 SLE patients with positive aPL but
no history of thromboembolism with 144 age- and sex-matched SLE patients
with negative aPL and followed them for approximately nine years [3].
Compared with the aPL-negative patients, aPL-positive patients had higher
 rates of thrombosis (8 versus 20 percent; hazard ratio [HR] after adjustment
for smoking and aspirin use, 3.88, 95% CI 1.82-8.23).

●Patients with obstetric APS but no history of thrombosis – Several studies

have reported an increased risk of a first thrombotic event in individuals with
obstetric APS [10-12]. In a prospective observational study including 1592 women
who had experienced pregnancy loss fulfilling obstetric criteria for APS but who
had not sustained a prior thrombotic event, women who tested positive for aPL
were more likely to sustain a subsequent thrombotic event compared with two
other groups of women who either tested positive or negative for an inherited
thrombophilia (eg, factor V Leiden) [13]. In addition, the higher rate of thrombotic
events in the group of women with aPL was observed despite the use of low-
dose aspirin prophylaxis in all patient groups. In a retrospective study of 115
women diagnosed with obstetric APS, 12 (10.4 percent) women developed
thrombotic events over a mean follow-up time of 10.91±4.47 years [14]. Most of
the women sustained an arterial event, three with stroke and six with a transient
ischemic attack. An important limitation to the study was that other risk factors for
thrombosis were not included in the analysis.

Is there a role for primary prophylaxis?

aPL without clinical criteria for APS — We suggest against the routine use of an
antithrombotic medication (aspirin or anticoagulant) for primary thrombosis prevention
in patients with aPL (with or without SLE) who do not have APS, unless it is appropriate
for other reasons such as cardiovascular risk reduction. All of the non-aPL thrombosis
risk factors should be addressed and eliminated when possible. (See "Aspirin in the
primary prevention of cardiovascular disease and cancer".)

Our approach to patients with aPL without a history of thrombosis is largely based on
clinical experience and observational studies. Although some retrospective studies
suggest that the use of low-dose aspirin is protective against first thrombosis in aPL-
positive patients with or without SLE, the effectiveness of aspirin alone has not been
demonstrated in randomized clinical trials. In addition, the protective role of aspirin
against cardiovascular events and cancer in the general population is highly
individualized based on the expected benefit and the risks of bleeding. The general
population prevention guidelines (eg, American Heart Association guidelines [15])
should play a role in the decision to use low-dose aspirin, regardless of whether or not
the patient has SLE, particularly since no lupus-specific cardiovascular disease
prediction tool exists [16-18].

A few of the larger studies that have evaluated the role of primary prophylaxis
with aspirin or aspirin plus low-intensity warfarin among individuals who are aPL-
positive have shown that any benefit, if present, is likely to be small:

●A 2014 meta-analysis that evaluated the effect of aspirin in 1208 individuals with
aPL (some had SLE and some did not) found a protective effect with low-dose
aspirin (odds ratio [OR] for first venous or arterial thrombosis, 0.50; 95% CI 0.27-
0.93) [19]. However, all but one of the 11 studies included were observational, and
 there was significant heterogeneity in the studies. In addition, one of the subgroup
analyses demonstrated that low-dose aspirin was only protective against arterial
thrombosis, and another subgroup analysis found that the protective effect of
aspirin was only statistically significant in retrospective (but not prospective)
studies.

●A follow-up meta-analysis of observational studies involving 497 SLE and non-

SLE patients with an isolated positive aPL without a history of thromboembolism
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) [20]. 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). However, several important studies were
excluded from this meta-analysis.

●The 2007 Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study is the

only double-blind randomized clinical trial to evaluate the role
of aspirin prophylaxis in aPL-positive patients; this trial did not find a protective
effect of aspirin, but the number of events were small [2]. In this trial, 98
individuals with persistent aPL positivity but no history of thromboembolic disease
or pregnancy morbidity were randomized to receive aspirin (81 mg daily) or
placebo for a mean of 2.3 years. Approximately two-thirds of these individuals had
SLE. Three patients in the aspirin-treated group developed thrombosis (two
venous and one arterial), compared with none in the placebo group (HR 1.04,
95% CI 0.69-1.56).

●A cohort study (described above) that compared 144 SLE patients with positive
aPL but no history of thromboembolism with 144 age- and sex-matched SLE
patients without aPL found that the duration of low-dose aspirin therapy had a
protective role against thrombosis in aPL-positive patients (HR per month 0.98,
95% CI 0.96-0.99), although the hazard ratio barely met statistical significance [3].

●The potential role of adding warfarin to aspirin in individuals with SLE and aPL
was evaluated in a 2014 trial that randomly assigned 166 aPL-positive patients
with SLE and/or obstetric morbidity 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 [21]. 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 alone.

APS based on pregnancy morbidity — We suggest against the use of an

antithrombotic medication (aspirin or anticoagulant) to prevent first thrombosis in
patients diagnosed with APS based on a prior pregnancy morbidity, unless it is
recommended for other reasons such as cardiovascular risk reduction. This approach
is largely based on the lack of evidence demonstrating a protective effect of aspirin or
anticoagulation for primary thrombosis prevention in women with obstetric APS. A
retrospective analysis of 65 patients with a history of a pregnancy found that the risk of
a subsequent thrombotic event after a mean follow-up of eight years was 10 and 59
percent with and without prophylactic low-dose aspirin, respectively [17]. While this
suggested that low-dose aspirin prophylaxis may be effective in this subgroup of APS
patients, limitations to the study included the fact that few confounders (such as other
risk factors for thrombosis) were included in the analysis and compliance with aspirin
treatment was not confirmed. More data are needed to clarify the use of low-dose
aspirin in this population.

The role of thromboprophylaxis in women during pregnancy and the peripartum period
who are diagnosed with APS based on a prior pregnancy morbidity is discussed in
detail separately. (See "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women", section on 'Management of APS during pregnancy'.)

TREATMENT OF ACUTE THROMBOSIS

General principles and choice of anticoagulation — The mainstay of treatment for

acute thromboembolism in a patient with antiphospholipid syndrome (APS) is
anticoagulation. Typically, this involves heparin overlapped with warfarin followed by
indefinite warfarin therapy in most patients. The rationale for indefinite therapy is the
high rate of recurrent thrombosis, although the number of risk-stratified studies is
limited. (See "Clinical manifestations of antiphospholipid syndrome", section on
'Recurrent thrombotic events'.)

Following stabilization and initial interventions for an acute thrombosis, we suggest

anticoagulation with warfarin rather than a direct oral anticoagulant (DOAC;
eg, apixaban, dabigatran, edoxaban, rivaroxaban) based on the lack of data regarding
efficacy and safety of the DOACs in APS patients (see 'Direct oral
anticoagulants' below). Warfarin is not used during pregnancy due to risks of
teratogenicity; thus, any individual with APS who becomes pregnant is treated with low-
molecular-weight heparin (LMWH) rather than warfarin, as discussed separately.
(See "Antiphospholipid syndrome: Pregnancy implications and management in
pregnant women" and "Use of anticoagulants during pregnancy and postpartum".)

The therapy for thromboembolic manifestations of APS is the same regardless of

whether the disorder is classified as primary APS or whether it occurs in the presence
of systemic lupus erythematosus (SLE) or another systemic autoimmune disease. In
cases of severe, widespread thromboembolic complications (catastrophic APS
[CAPS]), additional considerations may apply. (See 'Treatment of catastrophic
antiphospholipid syndrome' below.)

Acute VTE — For acute venous thromboembolic (VTE) events in patients with APS,
the first therapy is usually heparin. LMWH has replaced unfractionated heparin as the
standard of care for most patients. (See "Overview of the treatment of lower extremity
deep vein thrombosis (DVT)".)
Heparin (unfractionated heparin or LMWH) is usually overlapped with warfarin for a
minimum of four to five days, until the international normalized ratio (INR) is in the
therapeutic range (ie, prothrombin time [PT] INR of 2 to 3) for two consecutive days
[22]. In many cases, heparin and warfarin can be initiated on the same day. Long-term
anticoagulation for patients with VTE is discussed further below. (See 'Long-term
anticoagulation' below.)

Acute arterial thrombosis or thromboembolism — This initial stabilization and

management of stroke, myocardial infarction (MI), or other acute arterial
thromboembolic event in individuals with APS is not different from those without APS,
and is discussed in detail in separate topic reviews:

●Acute stroke (see "Initial assessment and management of acute

stroke" and "Approach to reperfusion therapy for acute ischemic
stroke"and "Antithrombotic treatment of acute ischemic stroke and transient
ischemic attack")

●Acute MI (see "Overview of the acute management of non-ST elevation acute

coronary syndromes" and "Overview of the acute management of ST-elevation
myocardial infarction")

●Retinal artery occlusion (see "Central and branch retinal artery occlusion")

●Renal artery occlusion (see "Renal infarction")

●Mesenteric artery occlusion (see "Acute mesenteric arterial occlusion")

Following stabilization and initial interventions for an acute thrombosis, almost all
patients require long-term anticoagulation due to the increased risk of recurrent events.
(See 'Long-term anticoagulation' below.)

SECONDARY THROMBOSIS PREVENTION

Long-term anticoagulation — Secondary thrombosis prevention with long-term

anticoagulation is the mainstay of therapy for antiphospholipid syndrome (APS)
patients due to the high rate of recurrent thrombosis. We generally treat venous and
arterial thrombosis in men and nonpregnant women with APS in the same way with
standard-intensity warfarin. For patients with arterial thrombosis, low-dose aspirin may
be added in selected patients with additional cardiovascular risk factors.

Secondary thrombosis prevention for women with APS during pregnancy is discussed
separately. (See "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women", section on 'Antithrombotic therapy'.)

Venous thrombosis — For patients with venous thromboembolism (VTE), we

recommend anticoagulation with warfarin with a target international normalized ratio
(INR) of 2.5 (range, 2 to 3) rather than a higher INR range. Our approach is generally
consistent with various guideline documents [23-25]. As noted above, individuals who
are pregnant or become pregnant are treated with low-molecular-weight heparin
(LMWH). (See 'General principles and choice of anticoagulation' above.)

Evidence to support standard-intensity warfarin with a target INR of 2 to 3 rather than a

higher INR in individuals with APS and VTE comes from two randomized trials and
additional observational studies.

●In a trial from 2003, 114 patients with antiphospholipid antibodies (aPL) and a
previous venous 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 [26]. There was no significant difference in the
rate of recurrent thrombosis for standard- versus high-intensity warfarin (3.4
versus 10.7 percent, respectively). 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 venous or arterial
thromboses were randomly assigned to receive warfarin at standard-intensity (INR
2 to 3) or high-intensity (INR 3.0 to 4.5) for 3.6 years [27]. There were no
significant differences in the rates of recurrent thrombosis (5.5 and 11.1 percent
for the standard- and high-intensity treatment groups, respectively) and no
significant between-group differences in major bleeding episodes (eg, fatal,
intracranial, retroperitoneal, or associated with need for blood transfusion or
surgery), although high-intensity therapy was associated with an increase in minor
bleeding episodes.

●A retrospective study involving 66 individuals with APS (half of whom also had
systemic lupus erythematosus [SLE]) treated with warfarinto 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) [28]. There were four major
bleeds, none 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).
(See "Management of warfarin-associated bleeding or supratherapeutic INR",
section on 'Bleeding rates'.)

Arterial thrombosis — The optimal management of APS patients with arterial events
is less clear, and consensus among experts is lacking [23,29]. In patients with arterial
thrombosis, we suggest the use of standard-intensity warfarin (INR range, 2 to 3) with
the addition of low-dose aspirin in selected patients with additional cardiovascular risk
factors. Our approach differs from the guidelines by the 13th International Congress on
Antiphospholipid Antibodies in which it was recommended that patients with definite
APS and an arterial thrombosis receive either warfarin at an INR >3.0 or low-dose
aspirin plus standard-intensity warfarin (INR range, 2 to 3) [23]. However, there was a
lack of consensus among the experts in the group, and several felt that standard-
intensity warfarin was equally valid in this setting.

There are limited data to help guide the optimal approach of anticoagulation in patients
with APS who had an arterial event. Data to support standard-intensity anticoagulation
with warfarin are described above in the randomized trials, in which almost 25 percent
of the thromboses in each of the studies were arterial [26,27] (see 'Venous
thrombosis' above). 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 (3.8 percent; 4 arterial and 1 venous) occurring at an INR >3 compared with an
INR <3 (23 percent; 13 arterial and 16 venous) [30]. These findings favor a higher INR
goal for patients with arterial events; however, this has never been evaluated in a
randomized trial.

Based on the lack of data on the management of patients with APS and ischemic
stroke, the optimal approach in these patients is unknown. In patients with definite
APS, they are generally managed in the same way as those with an arterial thrombosis
described above. There was only one randomized study that compared single
antiplatelet therapy with a combination of antiplatelet therapy and standard-intensity
anticoagulation therapy for secondary prevention in 20 patients with ischemic stroke
and APS [31]. After a mean follow-up of approximately four years, the cumulative
incidence of stroke in patients with antiplatelet treatment was higher than when
compared with patients receiving the combination of antiplatelet and anticoagulation
therapy. However, this study did not compare the use of standard-
intensity warfarin alone. In addition to the small size of the study, other important
limitations include the lack of data regarding the actual number and type of events in
each group.

In selected older adults with ischemic stroke who do not have definite APS but instead
have low aPL titers, low-dose aspirin alone may be appropriate. This approach is
based on data from the warfarin versus aspirin recurrent stroke study (WARSS), in
which individuals with stroke (mean age, 62.5 years) from the general population were
randomly assigned to receive either warfarin (target INR 1.4 to 2.8) or aspirin (325 mg
daily) for secondary prevention of ischemic stroke, and followed patients for
approximately two years [32]. In a subgroup analysis that included 1770 patients,
positivity for both anticardiolipin (aCL) and lupus anticoagulant (LA) was associated
with a higher event rate (32 percent) than for patients who tested negative for both
antibodies (24 percent), but the risk was not reduced by treatment with warfarin versus
aspirin. Of note, these patients had only one measurement of aPL as part of the study,
and therefore did not meet criteria for the diagnosis of APS. In addition, many patients
were older and had other cardiovascular risk factors. Thus, it is unclear whether these
results can be generalized to younger patients with APS and stroke.

Reduction of reversible risk factors — In addition to anticoagulation, attention

should be paid to minimizing the contribution of reversible risk factors for recurrent
thrombosis. During the perioperative period, this may include minimizing the period
when patients are off anticoagulation, initiating early ambulation, and other measures
to reduce venous stasis. (See "Perioperative management of patients receiving
anticoagulants".)

Estrogen-containing hormonal contraception should be avoided. (See "Contraceptive

counseling for women with inherited thrombophilias", section on 'Personal history of
venous thrombosis'.)

Can anticoagulation be stopped? — For most individuals with APS and a history of
an unprovoked thrombotic event, we recommend lifelong anticoagulation based on the
high likelihood of recurrence in the untreated patient 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. Of note, in patients with persistent LA test performed off
anticoagulation and/or moderate- to high-titer aCL/anti-beta2-glycoprotein (GP)-I, aPL
usually do not disappear during long-term follow-up. Thus, aPL should be repeated if
there is a consideration to stop anticoagulation; however, it should not be the only
determinant of the decision.

Evidence from retrospective series report 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 [33-35]. 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
six randomized trials and two cohort studies) found a trend towards an increased risk
for VTE recurrence after stopping anticoagulation that did not meet statistical
significance [36]. 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 play an important role in risk
stratification for recurrent thrombotic events. A small 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 [37]. In two 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 [38,39]. 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.

Recurrent thromboembolism despite adequate anticoagulation — Recurrent

thromboembolism in an individual with antiphospholipid syndrome (APS) who is being
treated with an anticoagulant is relatively rare, and often there are unique
circumstances that must be considered. There are several possible interventions for
patients who have a recurrent thrombotic event while receiving anticoagulation. The
choice among these must be individualized. As examples:

●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.

●If the recurrent thrombosis occurred despite a documented adequate

international normalized ratio (INR; range, 2 to 3) and without an additional major
thrombosis risk factor (eg, recent surgery), 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.

●An alternative approach is switching from warfarin to a low-molecular-weight

heparin (LMWH) (see "Warfarin and other VKAs: Dosing and adverse effects",
section on 'Transitioning between anticoagulants/bridging'). 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 is
largely based on our experience and data from a small series that showed
successful use of LMWH after initial warfarin failure [40].

●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, hydroxychloroquine (HCQ), and/or statin drugs, as discussed below.
(See 'Immunomodulatory agents' below.)

It should be noted that there are no data from randomized trials documenting the
superiority of any of these approaches in this setting.

ADDITIONAL CONSIDERATIONS WITH ANTICOAGULATION — Individuals with

antiphospholipid syndrome (APS) may encounter additional challenges with monitoring
due to the effects of the antiphospholipid antibodies (aPL) on the activated partial
thromboplastin time (aPTT) and prothrombin time (PT)/international normalized ratio
(INR) assays used to monitor unfractionated heparin and warfarin respectively. It is
especially important to obtain a baseline PT/INR and aPTT before starting
anticoagulation in APS so that a baseline prolonged PT or aPTT is not misinterpreted
as an effect of an anticoagulant. Options for monitoring in these settings are presented
below. (See 'Challenges in aPTT monitoring' below and 'Challenges in PT/INR
monitoring' below.)

Some individuals with APS may have concurrent thrombocytopenia, which may
increase concerns about bleeding. In general, we will administer an anticoagulant as
long as the platelet count exceeds 50,000 to 60,000/microL and is not declining;
anticoagulation at lower platelet counts may also be appropriate. Clinical judgment that
weighs the risks and benefits of anticoagulation for each patient is required, especially
with lower platelet counts. Thrombocytopenia does not reduce the risk of thrombosis in
APS and should not be interpreted to have a protective effect [41].
(See 'Thrombocytopenia' below.)

Additional information regarding the administration of heparin and warfarin, adverse

effects, and treatment of bleeding are presented separately:

●Heparin administration and adverse effects (see "Heparin and LMW heparin:
Dosing and adverse effects")

●Warfarin administration and adverse effects (see "Warfarin and other VKAs:
Dosing and adverse effects" and "Biology of warfarin and modulators of INR
control")

●Treatment of bleeding (see "Heparin and LMW heparin: Dosing and adverse
effects", section on 'Bleeding' and "Management of warfarin-associated bleeding
or supratherapeutic INR")

Challenges in aPTT monitoring — The aPTT is used to monitor therapeutic-

dose unfractionated heparin; routine monitoring is not required for low-molecular-
weight heparin (LMWH).

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

Challenges in PT/INR monitoring — 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 [42,43]. This 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 titrate out the LA
activity [44]. In individuals with a baseline prolongation of the PT/INR, however, this
prolongation in the absence of an anticoagulant should not be interpreted to mean that
the patient is adequately anticoagulated, as this can be 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
[42,44,45].

●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 [42,45,46]. 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 [42,45]. However, such an assay has not been
developed and validated for warfarinmonitoring, 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'.)

Another option is to use a different anticoagulant. However, there is insufficient

evidence for equivalent efficacy or safety of direct oral anticoagulants (DOACs) in
individuals with APS, and lifelong use of a parenteral anticoagulant such as LMWH
imposes significant costs and burdens on the patient. (See 'Direct oral
anticoagulants' below.)

Monitoring — 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".)

In addition, in individuals with no other systemic autoimmune diseases who are

otherwise tolerating anticoagulation well, we generally see the patient once or twice a
year. This can be combined with anticoagulation monitoring or done separately.
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 renal function. (See "Warfarin and other VKAs:
Dosing and adverse effects", section on 'Outpatient management'.)

After the confirmation of persistent aPL positivity, repeat aPL testing is generally not
indicated unless it will help with future treatment decisions (see 'Can anticoagulation be
stopped?' above). Patients who are symptomatic from organ-system involvement (eg,
cardiac symptoms) should undergo appropriate evaluations based on their symptoms.
(See 'Management of noncriteria manifestations' below.)

MANAGEMENT OF NONCRITERIA MANIFESTATIONS — Although the main focus

of the treatment of antiphospholipid syndrome (APS) is management and prevention of
thrombosis, there are other "noncriteria" manifestations of APS that 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
include manifestations such as cardiac valve disease, central nervous system
involvement, renal disease, hemolytic anemia, and thrombocytopenia (see "Clinical
manifestations of antiphospholipid syndrome", section on 'Clinical manifestations'). We
discuss our approach below to managing the noncriteria manifestations of
antiphospholipid antibodies (aPL) in patients with or without history of thrombosis.
(See "Diagnosis of antiphospholipid syndrome", section on 'Diagnosis' and "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
APS patients for cardiac valvulopathy unless they are symptomatic or a new murmur is
appreciated on cardiac examination. Cardiac imaging is driven by clinical suspicion of
NBTE such as a new murmur or a thromboembolic event. (See "Nonbacterial
thrombotic endocarditis", section on 'Imaging' and "Nonbacterial thrombotic
endocarditis", section on 'Echocardiography'.)

In individuals with APS who have cardiac involvement, antiplatelet therapy

and warfarin do not necessarily cause regression of the valvular lesions, but these
therapies may prevent clinical embolic events [47]. In the absence of chronic warfarin
treatment due to a history of thrombosis, despite lack of strong data, the majority of
aPL-positive patients are treated with low-dose aspirin. In patients at high risk for
embolic disease (eg, with vegetations) or who have had a myocardial infarction (MI),
anticoagulation should be initiated.

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). In addition, if there is embolization despite anticoagulation,
surgical consultation may be necessary.

Our approach is consistent with the following recommendations for different types of
cardiac involvement made in a 2003 consensus report on cardiac disease in APS [48]:

●Low-dose aspirin (eg, 81 mg daily) alone for those with echocardiographic

evidence of valvular thickening without clinical features of systemic embolization.

●Anticoagulation (eg, heparin and/or warfarin, international normalized ratio [INR]

2 to 3) for those with vegetations, systemic embolization, or MI.

The 2012 American College of Chest Physicians (ACCP) guidelines recommend

anticoagulation and control of the underlying disease for individuals without APS who
have NBTE with systemic or pulmonary emboli [49]. 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".)

Central nervous system manifestations — Management of stroke in patients with

APS is discussed above. (See 'Acute arterial thrombosis or thromboembolism' above.)

In addition to stroke, individuals with APS can develop white matter lesions on
magnetic resonance imaging (MRI) that are suggestive of a vasculopathy, migraine,
cognitive defects, seizures, and other findings (see "Clinical manifestations of
antiphospholipid syndrome", section on 'Neurological involvement'). If there is no
clinical suspicion of an ischemic stroke but white matter lesions consistent with APS
are seen on MRI, the role of low-dose aspirin is controversial; there are no data for or
against aspirin. Thus, these 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".)
Renal disease — Renal complications of APS include aPL-nephropathy, acute renal
failure, thromboses of arteriovenous grafts in patients on hemodialysis, and intrarenal
and systemic thromboses in patients with a renal transplant. Management of these
complications are discussed in detail 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 in individuals with APS may also

occur, with severe thrombocytopenia and microangiopathic hemolytic anemia (MAHA;
inferred from the presence of schistocytes (picture 1) on the peripheral blood smear). In
some cases, these individuals have severe deficiency of the ADAMTS13 protease,
consistent with acquired, autoimmune thrombotic thrombocytopenic purpura (TTP)
[50,51]. It is not clear whether APS increases the risk of acquired TTP or if these case
reports merely demonstrate the association of two autoimmune conditions in the same
patient [52,53]. In other cases, the patient may have catastrophic APS (CAPS),
characterized by widespread thrombotic disease with multiorgan failure. (See "Clinical
manifestations of antiphospholipid syndrome", section on 'Hematologic
abnormalities' and "Acquired TTP: Clinical manifestations and diagnosis".)

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 heparin-induced
thrombocytopenia (HIT) or immune thrombocytopenia (ITP). 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 above 30,000/microL. For those patients who do require treatment,
immunosuppression is used, similar to individuals without APS. The decision to
use immunosuppressive therapy, choice and sequence of therapies, and
monitoring of response is discussed in detail separately. However, unlike
individuals without APS, in APS we are more likely to use rituximab rather than
splenectomy due to the increased risks associated with surgery in this population
(eg, perioperative anticoagulation management, potential risk for precipitating
CAPS). (See "Immune thrombocytopenia (ITP) in adults: Initial treatment and
prognosis" and 'Immunomodulatory agents' below.)

Other aspects of the evaluation are described in detail separately. (See "Approach
to the adult with unexplained thrombocytopenia".)
 •Asymptomatic, mild thrombocytopenia – Mild decreases in platelet
counts (eg, platelet count in the range of 80,000 to 150,000/microL) are
frequently encountered in patients with aPL and/or systemic lupus
erythematosus (SLE). These patients are likely to have thrombocytopenia
due to an immune mechanism. In individuals with mild thrombocytopenia, the
platelet count can typically be followed with complete blood counts (CBCs)
every three to six months, or more frequently if new symptoms of bruising or
bleeding develop. (See "Clinical manifestations of antiphospholipid
syndrome", section on 'Hematologic abnormalities' and "Hematologic
manifestations of systemic lupus erythematosus", section on
'Thrombocytopenia'.)

•Severe thrombocytopenia/bleeding – The risk of bleeding increases with

severe thrombocytopenia, especially if the platelet count is <10,000/microL.
For individuals with a platelet count <10,000/microL and/or clinically
significant bleeding, platelet transfusion is likely to be indicated regardless of
the underlying cause, although there may be cases of immune platelet
destruction (mechanism similar to ITP) in which the platelet count may not
increase dramatically with platelet transfusions. (See "Clinical and laboratory
aspects of platelet transfusion therapy", section on 'Indications for platelet
transfusion'.)

•Possible TMA – For those with evidence of a TMA, the possibility of TTP or
drug-induced TMA should be evaluated; plasma exchange for a presumptive
diagnosis of TTP may be appropriate while awaiting the results of diagnostic
testing. (See "Approach to the patient with 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, and 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 (table 2). (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,
and 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 [54,55]. 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".)

As noted above, thrombocytopenia does not reduce the risk of thromboembolism in

individuals with APS [56,57]. Clinical judgment is required that weighs the risks and
benefits of anticoagulation for each patient, especially with lower counts.
(See 'Additional considerations with anticoagulation' above.)

LIMITED ROLE OF ALTERNATIVE THERAPIES — Management of antiphospholipid

syndrome (APS) patients may be complicated by fluctuating international normalized
ratio (INR) levels or major bleeding events. Thus, alternative therapeutic options may
be considered in selected cases with the caveat that there is insufficient evidence to
support any one approach.

Direct oral anticoagulants — We do not use a direct oral anticoagulant (DOAC;

eg, dabigatran or direct factor Xa inhibitor [apixaban, edoxaban, rivaroxaban]) to treat
APS. There has been interest in the use of DOACs for APS due to their convenience,
lack of need for laboratory monitoring, and decreased risk of bleeding [58]. However,
there are no high-quality data demonstrating equivalent efficacy or safety of DOACs in
individuals with APS.

●A 2016 systematic review of available case reports of patients with APS treated
with DOACs identified 122 patients, among whom 19 experienced a recurrent
thrombosis during treatment with a DOAC [59]. It was noteworthy that positivity of
all three laboratory criteria for APS was associated with a 3.5-fold increased risk of
recurrent thrombosis.

●In a subsequent 2016 trial, 110 patients with APS and a history of venous
thromboembolism (VTE) who had been taking warfarin for at least three months
were randomly assigned to continue warfarin (target INR 2.5) or switch to the
direct factor Xa inhibitor rivaroxaban at standard doses [60]. The primary aim was
to demonstrate that the intensity of anticoagulation achieved with rivaroxaban was
not inferior to that of warfarin using thrombin generation testing at 42 days; the
outcome measure was percentage change in endogenous thrombin potential
(ETP), a surrogate marker that has been shown to decrease in patients taking
anticoagulant therapy [61]. Secondary outcome measures compared clinical
efficacy, safety, quality of life, and laboratory measures of compliance in both
patient groups. The study showed that the ETP significantly increased in the
patients switched to rivaroxaban and did not reach the noninferiority threshold.
Although there was no increase in thrombotic events for patients in the
rivaroxaban arm compared with the warfarin arm, the study was not powered
sufficiently for this secondary outcome to be significant.

The 15th International Congress on Antiphospholipid Antibodies Task Force on APS

Treatment Trends published in 2017 concluded that there is insufficient evidence to
make recommendations regarding DOAC use in APS [62]. The trial
using rivaroxaban in APS described above suggests that rivaroxaban might be useful
in selected APS patients with a single VTE requiring standard intensity anticoagulation;
however, this needs to be confirmed with additional studies using clinical outcome
measures.

Exceptions to the avoidance of DOACs in APS may include individuals who cannot
tolerate warfarin and otherwise would not be treated with any anticoagulant. In these
settings, it is important to inform the patient that evidence for this approach is lacking,
and the risks are not well characterized [58,63].

Additional information about DOACs is presented separately. (See "Direct oral

anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects".)

Immunomodulatory agents — APS is an autoimmune disorder; the role of

immunomodulatory agents for the treatment of APS has thus been proposed [64].
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) picture. (See 'Thrombocytopenia' above.)

●Rituximab – Rituximab can be used in antiphospholipid antibody (aPL)-positive

patients with hematologic manifestations or a TMA picture [62]; 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 [65-67]. In addition, a pilot open-label phase 2 trial for
the treatment of noncriteria manifestations of APS (ie, thrombocytopenia, skin
ulcers, and cognitive dysfunction) included 19 patients and found that rituximab
was well tolerated and effective in some patients; of note, rituximab had no effect
on aPL levels in this study [68]. (See 'Management of noncriteria
manifestations' above.)

●Hydroxychloroquine – HCQ can be used as an additional treatment in difficult-to-

treat APS patients. HCQ is used routinely in the treatment of systemic lupus
erythematosus (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 [3,5,69].

●Statins – Statins can be used as an additional treatment in difficult-to-treat APS

patients. Limited data suggest that statins may have a beneficial effect for APS
patients by reducing proinflammatory and prothrombotic markers [70-72].
However, there are insufficient data to recommend the routine use of statins in
patients with APS in the absence of hyperlipidemia.
TREATMENT OF CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME — A small
subset of patients with antiphospholipid syndrome (APS) may develop widespread
thrombotic disease with organ damage, referred to as catastrophic APS (CAPS) [73].
The clinical manifestations and diagnosis of CAPS are discussed in detail separately.
(See "Clinical manifestations of antiphospholipid syndrome", section on 'Catastrophic
APS'.)

General principles — Early diagnosis and aggressive therapy is essential to the

management of CAPS since the mortality remains high at approximately 30 percent
[74]. The treatment is generally directed at addressing thrombotic events and
suppressing the cytokine cascade. This typically involves a combination of
anticoagulants, systemic glucocorticoids, plasma exchange, and intravenous immune
globulin (IVIG) [75].

Our approach — The following is our general approach to the treatment of CAPS
[73,75-78]:

●Any identifiable infection that may have precipitated the CAPS should be treated
with the appropriate antibiotics.

●We use anticoagulation with heparin for treatment in the acute setting [79]. In
patients who are hemodynamically stable and without evidence of recurrent
thrombi or active bleeding, we transition to oral anticoagulation with warfarin [75].

●We give high-dose systemic glucocorticoids (eg, methylprednisolone 0.5 to 1 g

intravenously daily for three days) followed by oral or parenteral therapy with the
equivalent of 1 mg/kg of prednisone per day [75].

●In severe cases, we also use plasma exchange and/or IVIG (IVIG 400 mg/kg per
day for five days). When IVIG is used, it is usually administered after the last day
of plasma exchange to prevent the removal of IVIG by plasma exchange.

Therapeutic plasma exchange for CAPS has never been investigated in a randomized
trial, but observational data suggest that it improves survival [74,79,80]. As an
example, the largest retrospective analysis comes from the CAPS Registry, which
found that among 250 patients with CAPS, the highest rate of recovery of 78 percent
was achieved by the combination of anticoagulation, glucocorticoids, and plasma
exchange [74].

Although the optimal number of plasma exchange treatments has not been determined,
a predictable 95 percent lowering of both immunoglobulin (Ig)G and IgM anticardiolipin
antibody (aCL) was documented after five consecutive plasma exchange treatments
[81].

The rationale behind the use of plasma exchange in patients with CAPS is based upon
the concept that antiphospholipid antibodies (aPL) may be the prime mediators in the
thrombosis. Given that the half-lives of IgG and IgM antibodies are 22 and 5 days,
respectively, plasma exchange is able to rapidly remove these antibodies. A more
detailed discussion of therapeutic plasma exchange is presented separately.
(See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and
technology".)

There is no evidence that IVIG alone improves survival, although the combination with
plasma exchange is thought to be more effective for severe cases and cases with
associated thrombocytopenia. A systematic review of 342 case reports and small
series involving patients with CAPS found that those who received triple therapy with
anticoagulation, glucocorticoids, and either plasma exchange, IVIG, or both had
significantly lower mortality rates compared with treatment strategies that did not use
plasma exchange, IVIG, or both [77]. A discussion about the use of IVIG in the
treatment of autoimmune disorders is presented separately. (See "Overview of
intravenous immune globulin (IVIG) therapy".)

Although IVIG is generally well tolerated, it has been associated with thrombosis and
should be avoided when anticoagulation must be interrupted (eg, for bleeding).
Adverse effects of IVIG are discussed in more detail separately. (See "Intravenous
immune globulin: Adverse effects".)

Resistant CAPS — In patients with CAPS resistant to standard therapies, several

case reports have indicated that treatment with rituximab(monoclonal antibody against
CD20 on B cells) or eculizumab (monoclonal antibody against complement component
C5) may be effective [82,83]. In APS mouse models, activation of complement (C) is
required, and interaction of C5a with its receptor, C5aR, results in aPL-induced
inflammation, placental insufficiency, and thrombosis. Furthermore, anti-C5 antibody
and C5aR antagonist peptides prevent aPL-mediated pregnancy loss and thrombosis
in these models [84]. However, additional clinical evidence is needed before either of
these medications has a role in the management of CAPS without first attempting
anticoagulation, glucocorticoids, and plasma exchange. The following reports are
illustrative:

●A review of 20 patients from the CAPS registry suggests that rituximab may play
a role in patients with refractory CAPS [85]. Twelve of the patients were given
rituximab as second-line therapy due to poor response to the initial treatment,
whereas the other patients received it as first-line therapy. Fifteen patients
recovered from the acute CAPS episode, and four patients died at the time of the
event.

●In two patients with recurrent CAPS despite maximal anticoagulation,

immunosuppression, and plasma exchange, a benefit was shown
with eculizumab [82,86].

●Another patient with systemic lupus erythematosus (SLE) and IgA deficiency
who subsequently developed CAPS was treated with anticoagulation and
glucocorticoids but was not able to tolerate additional therapy with plasma
exchange and IVIG [87]. The hospital course was complicated by diffuse
pulmonary hemorrhage, and anticoagulation was stopped. However, once the
patient was given eculizumab, her condition improved within four days.
PROGNOSIS — The prognosis for patients with antiphospholipid syndrome (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 'Treatment of
catastrophic antiphospholipid syndrome' above.)

●APS – 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 of
1999 to 2009 [88]. During the 10-year study period, 419 patients (over 40 percent
of 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).

•127 women became pregnant (188 pregnancies) with 73 percent resulting in

one or more live births. The most common obstetrical 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. Causes of death included arterial and
venous thromboembolic events (eg, stroke, myocardial infarction [MI], pulmonary
embolism, CAPS), bacterial infection, and bleeding.

These data confirm that patients who survive the initial episode that leads to the
diagnosis of APS 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.

●CAPS – The prognosis for CAPS without treatment is poor. However, the
combination of anticoagulation, glucocorticoids, and plasma exchange with or
without intravenous immune globulin (IVIG) has been associated with recovery
rates ranging from 50 to 80 percent [74,79,80,89].

The majority of patients with CAPS who survive their initial illness remain free from
further thromboembolic events when treated long-term with warfarin. This was
illustrated in an observational study of 58 survivors followed for an average of 67
months [90]. Two-thirds had no recurrent clotting or emboli. Approximately 20
 percent had recurrent APS-related events, but none had another episode of
multiorgan failure. Among the recurrent thromboembolic events, 40 percent
occurred in a perioperative period. This reinforces the importance of attention to
minimizing the period without anticoagulation in these individuals.
(See "Perioperative management of patients receiving anticoagulants".)

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: The antiphospholipid

syndrome (Beyond the Basics)" and "Patient education: Warfarin (Coumadin)
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The role of primary thrombosis prevention is controversial in individuals with

antiphospholipid syndrome (APS) who have not had a thrombotic event (eg, those
with antiphospholipid antibodies [aPL] alone or those diagnosed with APS based
on aPL plus pregnancy morbidity). We suggest against routine use of an
antithrombotic medication (aspirin or anticoagulant) for primary thrombosis
prevention in these individuals (Grade 2C). However, low-dose aspirin may be
used if indicated for other reasons, such as aspirin for cardiovascular risk
reduction. The role of thromboprophylaxis in women during pregnancy and the
peripartum period who are diagnosed with APS based on a prior pregnancy
morbidity is discussed in detail separately. (See 'Primary thrombosis
prevention' above and "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women".)

●The mainstay of treatment for acute thromboembolism in a patient with APS is

anticoagulation. Typically this involves heparin overlapped with warfarin. For
secondary thrombosis prevention in individuals with APS, we suggest warfarin
rather than a direct oral anticoagulant (DOAC) (Grade 2C). This is based on a
lack of high-quality evidence that DOACs are as effective as warfarin in APS. For
individuals who are pregnant or become pregnant, low-molecular-weight heparin
(LMWH) is used instead of warfarin. (See 'Treatment of acute thrombosis'above
and 'Direct oral anticoagulants' above and "Use of anticoagulants during
pregnancy and postpartum".)

●Secondary thrombosis prevention with long-term anticoagulation is the mainstay

of therapy for APS patients due to the high rate of recurrent thrombosis.

•For individuals with venous thromboembolism (VTE), we recommend

anticoagulation with standard-intensity warfarin (international normalized ratio
[INR] range, 2 to 3) rather than a higher INR range (Grade 1B). (See 'Venous
thrombosis' above.)

•For arterial thromboembolism, data on the optimal therapeutic approach to

prevent recurrent thromboembolism are extremely limited, and the optimal
approach is less clear. For most patients with APS and arterial
thromboembolism, we suggest anticoagulation with warfarin (INR range, 2 to
3) alone (Grade 2C). Low-dose aspirin may be added to warfarin for selected
patients with arterial events who also have additional risk factors for
atherosclerotic vascular disease. Risk-benefit assessment is important in
arterial thromboembolism as some individuals may reasonably choose to use
another treatment approach as discussed above. (See 'Arterial
thrombosis' above.)

•Regardless of the anticoagulation strategy, reduction of reversible risk

factors is important. (See 'Reduction of reversible risk factors'above.)

•Anticoagulation should be continued indefinitely for most individuals with

APS and a history of an unprovoked thrombotic event. This is based on the
high likelihood of recurrence in the untreated patient and the potentially
devastating nature of recurrent thromboembolic events, especially arterial
events. (See 'Can anticoagulation be stopped?' above.)

●Some individuals with APS have a baseline prolonged activated partial

thromboplastin time (aPTT), making monitoring of heparin therapy difficult. Less
commonly, the baseline prothrombin time (PT) is prolonged. Our approaches to
monitoring anticoagulation in these individuals are described above.
(See 'Additional considerations with anticoagulation' above.)

●Recurrent thromboembolism in an individual with APS who is being treated with

an anticoagulant is rare, and often there are unique circumstances that must be
considered. The approach is individualized according to patient circumstances
and may include a higher target INR, switching to LMWH, or adding other
medications (eg, aspirin, an immunomodulatory agent). (See 'Recurrent
thromboembolism despite adequate anticoagulation' above
and 'Immunomodulatory agents' above.)
 ●Management of noncriteria manifestations of APS (clinical manifestations that
are not part of the revised Sapporo classification criteria (table 1) such as cardiac
valve disease, central nervous system involvement, renal disease, hemolytic
anemia, and thrombocytopenia) is challenging due to the diversity of features and
lack of data. Individuals with cardiac valve vegetations may be treated
with aspirin or anticoagulation if not already receiving it; those with white matter
lesions on brain magnetic resonance imaging (MRI) may be treated with aspirin in
some cases, and thrombocytopenia is managed as appropriate based on the
suspected underlying cause. (See 'Management of noncriteria
manifestations' above.)

●Catastrophic APS (CAPS; a rare, potentially life-threatening form of APS

characterized by widespread thrombotic disease with organ damage) is treated
with early and aggressive therapy that includes anticoagulation, glucocorticoids,
and, in severe cases, plasma exchange and/or intravenous immune
globulin (IVIG). (See 'Treatment of catastrophic antiphospholipid
syndrome' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge

Bonnie Bermas, MD, Peter Schur, MD, and Andre Kaplan, MD, who contributed to an
earlier version of this topic review.