Bonnie L Bermas, MD
Peter H Schur, MD
Andre A Kaplan, MD
David S Pisetsky, MD, PhD
Paul L Romain, MD
INTRODUCTION — The antiphospholipid antibody syndrome (APS) is defined by two major components:
- Presence in the serum of at least one type of autoantibody known as an antiphospholipid antibody (aPL). APL are directed against negatively-charged phospholipids, such as cardiolipin.
- The occurrence of at least one clinical feature from a diverse list of potential disease manifestations, the most common of which are categorized as venous or arterial thromboses, recurrent fetal loss, or thrombocytopenia.
Although most of the clinical manifestations of APS can occur in other disease populations, in the APS they occur by definition in the context of aPL. APL are directed against serum proteins bound to anionic phospholipids and may be detected as:
- Lupus anticoagulants
- Anticardiolipin antibodies
- Antibodies to ß2 glycoprotein-I
- Other antibodies, including those to prothrombin, annexin V, phosphatidylserine, phosphatidylinositol, and others
APS occurs either as a primary condition or as a secondary condition in the setting of an underlying disease, particularly disorders in the spectrum of systemic lupus erythematosus (SLE).
The treatment of the APS will be reviewed here. The pathogenesis, clinical manifestations, and diagnosis of APS are presented separately. (See “Pathogenesis of the antiphospholipid syndrome” and “Clinical manifestations of the antiphospholipid syndrome” and “Diagnosis of the antiphospholipid syndrome”.)
This review begins with a discussion of the current APS treatment modalities, and then considers specific clinical settings in which treatment must be addressed.
CURRENT THERAPIES — The therapy for the APS is largely the same regardless of whether the disorder is classified as primary APS or as being secondary to SLE. Current therapies for the APS include the following medications:
- Low molecular weight heparin
- Unfractionated heparin
- Antiplatelet agents
Treatment approaches to the catastrophic APS and investigational therapies are discussed below. (See ‘Catastrophic APS’ below and ‘Investigational treatments’ below.)
Heparin — The initial approach to thrombosis in the APS is identical to that of many other thromboses. For acute thrombotic events in patients with aPL, the first therapy is heparin. Low molecular weight (LMW) heparin has replaced unfractionated heparin as the standard of care for most thrombotic events. (See “Treatment of lower extremity deep vein thrombosis” and ‘Warfarin’ below.)
Heparin is usually given simultaneously with warfarin and is overlapped with warfarin for a minimum of four to five days until the International Normalized Ratio (INR) has been within the therapeutic range (2.0 to 3.0) for two consecutive days .
Heparin also plays a critical role in the treatment of the pregnant patient with the APS, because warfarin is contraindicated in early pregnancy. Treatment of the pregnant APS patient is reviewed separately. (See “Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome”, section on ‘Heparin/heparin with aspirin’ and “Anticoagulation during pregnancy”.)
Low molecular weight heparin — Several LMW products are now available for clinical use. Dosing requirements are individualized for each product . The advantages of LMW heparins over unfractionated heparin are reviewed separately. (See “Therapeutic use of heparin and low molecular weight heparin”.)
Many APS-related events can be managed on an outpatient basis (table 1) [3-9]. The following four criteria can help to identify patients with deep venous thrombosis (DVT) for whom outpatient treatment might not be appropriate :
- Massive DVT
- Symptomatic pulmonary embolism
- High risk of bleeding with anticoagulant therapy
- Presence of comorbid conditions or other factors that warrant hospital care
Unfractionated heparin — Unfractionated heparin is preferred to LMW heparin in certain circumstances. The major potential advantage of unfractionated heparin over LMW heparin is in the setting of hemorrhage (a rare complication of the APS). Unfractionated heparin can be reversed quickly with protamine, while LMW is not completely reversible with this approach. The major setting in which hemorrhage is due to APS is when antibodies to prothrombin are present. (See “Clinical manifestations of the antiphospholipid syndrome”, section on ‘Bleeding episodes’.)
Warfarin — Following stabilization of the patient, warfarin is begun. Warfarin is the standard of care for the chronic management of patients with the APS who are not pregnant. The current standard of care, developed through randomized controlled trials, is to maintain the INR between 2.0 and 3.0 [11,12]. However, aPL may create problems in monitoring of the INR (see ‘Problems in monitoring INR’ below).
Antiplatelet agents — The two antiplatelet agents that have been evaluated in patients with APS are aspirin and clopidogrel.
Aspirin — In retrospective series, aspirin has been of minimal or no benefit for the prevention of thrombotic APS manifestations in patients who have experienced previous events [13,14]. However, aspirin may be beneficial for prophylaxis in patients with aPL who do not have a history of thrombosis  (see ‘Prophylaxis’ below).
Clopidogrel — Clopidogrel has been reported to be useful in at least one case report and is recommended by some experts [16,17]. It may have a role in the treatment of APS and in the primary and secondary prophylaxis in individuals who are allergic to aspirin. However, there is no a priori reason for using clopidogrel over aspirin in the absence of contraindications to aspirin.
Hydroxychloroquine — Data from animal models and limited indirect evidence from studies in humans suggest that hydroxychloroquine is useful in APS:
- Hydroxychloroquine reduces the size and persistence of venous thrombi in a rodent model of the APS .
- In vitro data from a human study suggests that hydroxychloroquine reverses platelet activation induced by IgG aPL .
- In a cross-sectional study designed to analyze risk factors for the APS, 77 APS patients with thrombotic events and 56 asymptomatic aPL-positive patients were evaluated . In both univariate and multivariate analyses, hydroxychloroquine use was associated with a lack of thrombotic events.
An expert panel convened to review the issue of cardiac disorders associated with the APS suggested that hydroxychloroquine could be considered for cardiac protection . The potential utility of hydroxychloroquine in preventing APS-related events strengthens the case for the routine use of this medication in patients with SLE, particularly those known to have aPL. (See “Antimalarial drugs in the treatment of rheumatic disease”, section on ‘Antimalarials for the treatment of specific diseases’.)
SPECIFIC CLINICAL SETTINGS — The approach to treating APS varies with the clinical presentation.
Secondary prevention — A number of studies have evaluated the rate of recurrent thromboembolism after an initial event in patients with APS [13,14,21]. Considering all patients, regardless of the presence or absence of warfarin therapy, recurrent events were seen in up to 11 percent of patients per year; some patients had multiple recurrences. In two studies, the rates of recurrence among untreated patients were 29 and 19 percent per year, respectively [13,14]. The frequency of recurrent clinical events in patients with the APS and the potentially devastating nature of these events is a strong argument for lifelong anticoagulation in some patients (see ‘Duration of warfarin use’ below).
Prophylaxis — Issues regarding the role of prophylaxis for patients with aPL in the absence of clinical events has long been debated. Retrospective and prospective observational studies and controlled trials of aspirin for the prevention of thrombotic events in people with aPL who have no history of arterial or venous thromboembolism have had disparate results [22-25]. The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study consisted of two separate investigations involving patients who were asymptomatic but persistently aPL-positive :
- A multicenter, randomized, double-blind placebo-controlled clinical trial randomly assigned asymptomatic individuals who were persistently aPL-positive to receive placebo or 81 mg/day of aspirin. Forty-eight patients were randomized to aspirin, and 50 to placebo. Mean follow-up was 2.3 years.
- A separate observational and parallel study involved asymptomatic, persistently aPL-positive patients who were taking aspirin already or declined randomization. In this nonrandomized investigation, 61 individuals received aspirin and 13 did not. Mean follow-up was 2.46 years.
The majority of patients in both of these investigations had an underlying systemic autoimmune disease, most commonly SLE.
In the randomized trial, there was no difference between the two treatment groups in the incidence of acute thrombosis. The incidence rate among individuals in the aspirin group was 2.75 per 100 patient-years, compared with 0 per 100 patient-years among individuals in the placebo group.
In the observational portion of the APLASA study, the incidence rate of acute thrombosis was 2.70 per 100-patient years among individuals who took aspirin, compared with 0 per 100 patient years among those who did not.
Among the 13 thrombotic events observed in the combined randomized trial and observational APLASA study data, only one occurred in a patient who did not have additional risk factors for thrombosis (eg, hypertension, smoking, obesity, estrogen replacement therapy).
The conclusions of the APLASA trial were as follow:
- Asymptomatic individuals who are persistently positive for aPL have a low annual incidence of acute thrombosis.
- These individuals do not benefit from low-dose aspirin.
- Thrombotic events in this population are unlikely in the absence of additional risk factors for thrombosis.
SLE with aPL — Patients with SLE and aPL have an increased risk of thromboembolic disease and/or recurrent pregnancy loss. In two series of patients with SLE and aPL or a lupus anticoagulant, approximately 20 to 50 percent of patients met criteria for APS at 10- to 20-year follow-up [24,26,27]. Among patients with anticardiolipin antibodies, the higher the titer, the greater the risk of thrombosis [25,28].
The potential benefit of low-dose aspirin prophylaxis was illustrated in an observational study that followed 144 patients with SLE who were aPL-positive for a median of 104 months and compared them to a group of 144 patients with SLE who were aPL-negative . Seventeen of the aPL patients were LAC-positive, and 115 had IgG aCL antibodies.
- Thrombotic events developed in 29 of those who were APL-positive versus 11 in those aPL-negative.
- Those with thromboses were more likely to have repeatedly positive IgG (79 percent) than those without thromboses (37 percent).
- Eighty-seven of the aPL-positive patients took low dose aspirin; those with APL who took aspirin, and those who took it longer were less likely to have a thrombotic event.
- Hydroxychloroquine (101 of the aPL positive patients) did not prevent thrombotic events.
These observations suggest that in these longer studies (as compared with the APLASA study) low-dose asa does tend to significantly reduce the risk of thromboses in aPL-positive SLE patients.
The following approach is suggested in asymptomatic patients with aPL, with recognition that data supporting benefit are limited:
- In the absence of any contraindication to the use of aspirin, prophylactic therapy with a low-dose (81 mg/day) should be considered for patients with SLE, another underlying connective tissue disorder, or history of a miscarriage [29-31].
- Concomitant use of hydroxychloroquine (≤6.5 mg/kg per day) and low-dose aspirin is an option with SLE or a related connective tissue disorder .
- Women with aPL should avoid oral contraceptives, particularly those with a high estrogen content.
- Modifiable risk factors that predispose to thrombosis (eg, venous stasis, hypertension, hyperlipidemia, cigarette smoking) should be addressed .
Venous thromboembolism — The initial treatment of deep venous thrombosis (DVT) or pulmonary embolism (PE) in patients with APS is the same as that for idiopathic thromboembolic disease. The standard of care for both of these clinical complications is treatment with heparin, followed by warfarin. The general treatment approaches to these disease complications are discussed separately. (See “Treatment of lower extremity deep vein thrombosis” and “Treatment of acute pulmonary embolism”.)
Substantial debate has surrounded the intensity and duration of warfarin therapy in patients with APS.
Intensity of anticoagulation — Observational studies in the 1990s suggested that optimal anticoagulation regimens were those that maintained the INR between 3.0 and 4.0 [14,21]. However, the current standard of care for the long-term management of the APS is to maintain the INR between 2.0 and 3.0 for an initial venous thromboembolic event and at >3.0 for an initial arterial event or for recurrent venous thrombosis despite anticoagulation . This standard was defined by two major randomized trials [11,12].
In one trial, 114 patients with aPL and previous thrombosis were randomly assigned to receive either moderate- or high-intensity treatment with warfarin. For the moderate-intensity treatment group, the target INR was 2.0 to 3.0; for the high-intensity group, the target INR was 3.1 to 4.0 . The average attained INR was 2.3 and 3.3 in the two groups.
The following findings were noted at a mean follow-up of 2.7 years:
- The overall rate of recurrent thromboembolic events was 7 percent.
- The rate was numerically but not statistically greater in the high-intensity group (10.7 versus 3.4 percent, hazard ratio 3.1, 95% CI 0.6-15.0).
- One-half of the recurrent thrombotic events in both groups occurred when the INR was less than 2.0.
- Major 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 the second trial, 109 APS patients with previous thromboses were randomly assigned to either standard or high-intensity warfarin therapy (target INR 2.0 to 3.0 or 3.0 to 4.5, respectively) . The mean attained INR was 2.5 and 3.2 in the two groups.
The following major findings were noted at a mean follow-up of 3.6 years:
- Recurrent thrombosis occurred in 6 of 54 patients and 3 of 55 patients receiving high-intensity and moderate-intensity warfarin, respectively (11 versus 5.5 percent). This difference was not statistically significant (hazard ratio 1.97; 95% CI 0.49-7.89).
- Major bleeding episodes occurred in two and three patients in each group, but there was a significant increase in minor bleeding episodes with high-intensity therapy.
Thus, high-intensity therapy is associated with no demonstrable benefit and potential harm. The current standard of care for the long-term management of the APS is to maintain the INR between 2.0 and 3.0.
The presence of aPL antibodies may affect the INR causing fluctuations or artifactual prolongation. Approaches to monitoring warfarin anticoagulation in such cases is discussed below (see ‘Problems in monitoring INR’ below).
Duration of warfarin use — The optimal duration of anticoagulation for venous thromboembolic disease following a first event is uncertain in patients with APS. Lifelong therapy is prudent for many patients. In a prospective study of 412 patients with a first episode of venous thromboembolism, the presence of anticardiolipin antibodies at the end of six months of treatment was associated with a doubling of the risk of recurrent thrombosis (29 versus 14 percent) .
The authors of a 2006 systematic review concluded that anticoagulation is warranted for an indefinite period for patients with APS and venous thrombosis . Low-dose aspirin is warranted if warfarin therapy must be discontinued. (See “Therapeutic use of warfarin”.)
Treatment failure — If thrombotic events recur during warfarin therapy despite INR levels that are within the target range, the treatment alternatives include increasing the target INR (3.1 to 4.0) or adding low-dose aspirin. The choice between these options is based in part upon patient characteristics (eg, reliability to maintain a higher INR, concern about bleeding), since there are no good data on comparative efficacy. We prefer low-dose aspirin in view of the possible harm in the randomized trials from higher intensity warfarin [11,12]. A 2007 systematic review concluded that there was no role for the addition of low-dose ASA to warfarin therapy in patients with recurrent events and INR >3.0 .
Central nervous system manifestations — The major central nervous system manifestations of the APS are stroke and white matter lesions. (See “Clinical manifestations of the antiphospholipid syndrome”.)
Stroke — Guidelines issued in 2006 by the American Heart Association/American Stroke Association include the following recommendations :
- For cases of cryptogenic ischemic stroke or transient ischemic attack (TIA) associated with aPL, antiplatelet therapy is reasonable. A 2007 systematic review of thrombotic disorders associated with aPL also suggested antiplatelet secondary prophylaxis for those with a stroke and a single positive, rather than repeatedly positive, tests for aPL .
- For patients with ischemic stroke or TIA who meet the criteria for the APS, warfarin therapy with a target INR of 2.0 to 3.0 is reasonable. (We note that a higher target INR of 3.0 to 4.0 has been recommended by other authors .)
However, cryptogenic stroke or TIA in patients with aPL satisfies the diagnostic criteria for APS. Thus, in the setting of a confirmed and otherwise unexplained thrombotic event associated with aPL, we suggest warfarin therapy even in the absence of other APS manifestations.
For those patients with aPL and at high risk for strokes, such as those with SLE, hypertension, diabetes, and/or hyperlipidemia, ASA 81 mg/day is strongly recommended .
For those with recurrent strokes despite “adequate” anticoagulation with warfarin, the options include a higher INR, adding ASA 81 mg, or switching to heparin .
There are no data regarding recommendations for the treatment of other aPL-related neuropsychiatric symptoms.
White matter lesions — Central nervous system involvement in APS may be associated with high-intensity lesions on magnetic resonance imaging studies (MRI) that are suggestive of a vasculopathy. (See “Clinical manifestations of the antiphospholipid syndrome”, section on ‘Neurologic syndromes besides stroke’.)
For patients with aPL in whom there is no clinical suspicion of an ischemic or embolic stroke but who have white matter lesions on MRI that are consistent with the APS, low-dose aspirin therapy is a reasonable initial approach. Warfarin therapy may be appropriate in patients who, while on aspirin, develop documented cognitive deficits or clear progression of the white matter lesions on serial MRI .
Cardiac manifestations — Two major cardiac issues ensue from the APS: complications of cardiac valvulopathy, and myocardial infarction from coronary artery thrombosis. Cardiac valvulopathy due to nonbacterial thrombotic endocardial deposits can cause systemic embolic complications. Antiplatelet therapy and warfarin do not necessarily cause regression of the valvular lesions, but may prevent clinical events .
The following recommendations for different types of cardiac involvement were made in a consensus report :
- Low-dose aspirin (81 mg/day) is suggested for echocardiographic evidence of valvular thickening without clinical features of systemic embolization.
- Heparin followed by warfarin anticoagulation (target INR 2.0 to 3.0) is suggested for echocardiographic evidence of vegetations, clinical evidence of systemic embolization, or aPL-associated myocardial infarction.
Renal manifestations — Among the renal complications that can occur in the APS are acute renal failure, frequent thromboses of arteriovenous grafts in patients on hemodialysis, and intrarenal and systemic clotting events in patients with a renal transplant. These issues are discussed in detail elsewhere. (See “Antiphospholipid syndrome and the kidney”.)
Hematologic manifestations — Hematologic manifestations of the APS include thrombocytopenia and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS).
Thrombocytopenia — The mechanism of thrombocytopenia in the APS is believed to be the binding of aPL to platelet-associated phospholipids . Patients with aPL and mild thrombocytopenia generally require no therapy for the thrombocytopenia itself. However, these patients may be hypercoagulable even in the setting of severe thrombocytopenia [39,40]. (See “Clinical manifestations of the antiphospholipid syndrome”, section on ‘Thrombocytopenia’.)
There are few data suggesting that anticoagulation is an effective therapy for APS-associated thrombocytopenia. Although the optimal approach to patients with marked APS-associated thrombocytopenia remains uncertain, it is reasonable to treat such patients in a manner similar to those with chronic immune (idiopathic) thrombocytopenic purpura: eg, with glucocorticoids, rituximab, intravenous immune globulin, and other agents . (See “Treatment and prognosis of immune (idiopathic) thrombocytopenic purpura in adults”.)
Anecdotal success in the treatment of APS-related thrombocytopenia has been reported with danazol , low-dose aspirin , dapsone , and chloroquine .
Among patients with thrombocytopenia who develop a thromboembolic, we suggest LMW heparin and warfarin (goal INR 2.0 to 3.0) as in other patients with APS.
TTP/HUS — Data related to the treatment of APS- or SLE-associated TTP/HUS are few. The standard of care for both idiopathic TTP/HUS and TTP/HUS occurring in the setting of SLE is to employ plasma exchange. (See “Treatment of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”.)
Catastrophic APS — A small subset of patients with APS has widespread thrombotic disease with visceral damage, referred to as the “catastrophic” APS . Preliminary classification criteria for this disorder have been proposed (table 2).
The prognosis for such patients without treatment is poor. The prognosis may be better with intensive treatment. The combination of anticoagulation, glucocorticoids, and plasma exchange with or without intravenous immune globulin has been associated with recovery rates ranging from 50 to 80 percent [47-49].
A majority of patients with catastrophic APS who survive their initial illness remain free of 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 . 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. (See ‘Perioperative management’ below.)
Recommended management for patients with the catastrophic APS consists of the following [46,48,51]:
- Treatment of any identifiable disorder that may have precipitated the catastrophic APS (eg, infection).
- Anticoagulation with heparin in the acute setting, followed by long-term warfarin.
- High-dose glucocorticoids (eg, methylprednisolone 1 g intravenously daily for three days) followed by oral or parenteral therapy with the equivalent of 1 to 2 mg/kg of prednisone per day.
- If there are features of microangiopathy (eg, thrombocytopenia, microangiopathic hemolytic anemia), plasma exchange (see below) with or without IVIG (eg, 400 mg/kg per day for five days) are added to the above regimen.
Therapeutic plasma exchange (TPE) — Given that the half-lives of IgG and IgM antibodies are 22 and 5 days, respectively, and given that the anticardiolipin antibodies may be prime mediators in the thrombosis associated with CAPS, TPE, with its ability to rapidly remove these antibodies, becomes an appealing therapeutic option.
Although plasma exchange for CAPS has never been investigated in a prospective, randomized study, a review of the first 250 patients entered into the CAPS Registry noted that the combination of TPE, anticoagulants and steroids resulted in an overall 78 percent survival  leading the authors to conclude that this treatment combination should be the first line of therapy for patients with CAPS. Given that the available data suggests substantial improvement in survival [47-49], TPE can be considered in any patient presenting with CAPS .
Although the optimum number of plasma exchange treatments has not been determined, we have recently documented a predictable 95 percent lowering of both IgG and IgM anticardiolipin antibody after five consecutive plasma exchange treatments .
Pregnancy — Women with the APS are at increased risk for recurrent fetal loss, especially after 10 weeks of gestation. A detailed discussion of the treatment of pregnant women with the APS is presented separately. (See “Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome”.)
Perioperative management — Guidelines for perioperative management of patients with APS are based upon anecdotal experience. The following approach has been proposed :
- If warfarin is used preoperatively, it must be stopped a few days prior to surgery.
- For general surgery prophylaxis, 5000 units of unfractionated heparin or 30 to 40 mg of enoxaparin is given subcutaneously one or two hours preoperatively.
- For orthopedic surgery, LMW heparin is preferred.
If there are no immediate postoperative bleeding complications, warfarin can be resumed the evening after surgery. Prophylactic heparin is continued until the INR is in therapeutic range. (See “Management of anticoagulation before and after elective surgery”.)
COMPLICATIONS OF THERAPY — Anticoagulation may be associated with a number of challenges in monitoring and a significant risk of bleeding complications.
Problems in monitoring INR — Some patients with the APS have marked fluctuations in the INR that make monitoring of the degree of anticoagulation difficult . Factors that can affect the INR include:
- Time of day — Some of the variation may relate to testing at different times of day following the dose of warfarin. Whenever it is practical to do so, patients should have their blood drawn at the same time of day and in the same laboratory.
- Drug interactions — Some fluctuations of the INR are due to the concurrent use of medications that affect warfarin metabolism. Such an effect may be particularly true for acetaminophen , since this agent tends to be recommended to individuals with rheumatic diseases. The INR must be carefully monitored in patients taking these two drugs. (See “Therapeutic use of warfarin”, section on ‘Drug interactions’.)
- Antiprothrombin antibodies — Antiprothrombin antibodies may result in prolongation of the prothrombin time (PT) even before administration of warfarin. Such patients may present with bleeding as well as thrombosis. (See “Pathogenesis of the antiphospholipid syndrome”, section on ‘Antiprothrombin antibodies’ and “Acquired inhibitors of coagulation”, section on ‘Prothrombin inhibitors’.)
- Variations in thromboplastin reagents — Some of the variation in the INR may be due to the use of different thromboplastins in the PT assay employed by different laboratories [54,56]. One study determined the INR using eight different thromboplastin reagents in 43 patients with and 47 patients without lupus anticoagulants . Measurement of chromogenic factor X values, which are unaffected by aPL, were also assessed. A subset of six patients with lupus anticoagulants had widely varying results with one thromboplastin reagent (Innovin). In comparison, values of chromogenic factor X were identical between those with and without aPL.
- Effects of warfarin on coagulation factors — Warfarin primarily affects prothrombin, whose level is the most important determinant regarding the efficacy of warfarin . On the other hand, the INR reflects Factor VII levels much more so than prothrombin levels; Factor VII levels are not as affected by warfarin nearly as much as prothrombin levels .
- Lupus anticoagulants may interfere with the accurate determination of the INR .The solution to this problem varies according to local expertise and practice. Possibilities include:
- Measurement of chromogenic factor X levels or the prothrombin-proconvertin time instead of the INR.
- Measurement of F1 and/or F2 prothrombin fragment levels.
- Avoidance of thromboplastin reagents that provide varying results in the presence of aPL [54,56,58-60].
- Treating patients with LMW heparin or with lower dose warfarin plus aspirin in order to avoid the difficulties in maintaining a therapeutic INR .
- Measuring Factor II (prothrombin) level to establish therapeutic depletion of Factor II and determine a patient-specific INR. In practice this entails initial warfarin treatment to a target INR of 2-3, then determination of the Factor II level; a 15 to 25 percent range is therapeutic; if the Factor II level is >30 percent, the warfarin dose should be increased to a level that achieves therapeutic Factor II levels; once a therapeutic Factor II level is achieved the patient can be monitored by either Factor II levels or the corresponding INR .
Self-monitoring — Self-monitoring of anticoagulation using portable testing equipment at home is feasible for some patients. Such an approach may result in better control of the INR, especially for those with higher target INR values. Randomized trials have shown that appropriately trained patients who self-monitored and self-adjusted their oral anticoagulation had fewer thromboembolic events, fewer episodes of major bleeding, and a lower mortality compared with those undergoing standard monitoring. (See “Outpatient management of oral anticoagulation”, section on ‘Self-monitoring and self-management’.)
Bleeding during anticoagulant therapy — There are limited data on the risk of bleeding while on anticoagulant therapy for APS. In a retrospective study of warfarin anticoagulation in 66 patients (approximately one-half of whom had primary APS and the others SLE), a target INR of 3.5 was selected . Median follow-up in the cohort was five years. The following observations were noted:
- Four patients experienced major episodes of bleeding, but none resulted in death. Two retroperitoneal hemorrhages occurred in the setting of renal biopsies and there was one large rectal bleed and one intracranial hemorrhage.
- Major bleeding and intracranial bleeding occurred at rates of 6 and 1.5 per 100 patient-years, respectively.
- Despite the relatively intensive anticoagulation target, six patients had recurrent thrombotic events (9 per 100 patient-years).
As discussed above, two randomized trials showed no significant difference in the occurrence of major bleeding episodes between the groups that received moderate- versus high-intensity anticoagulation [11,12]. (See ‘Intensity of anticoagulation’ above.)
INVESTIGATIONAL TREATMENTS — Investigational therapies for the APS include autologous stem cell transplantation  and rituximab . To date, insufficient data on the use of these approaches exist to guide therapeutic recommendations.
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 of care when the patient presents with multisystem disease as seen in the catastrophic antiphospholipid syndrome (CAPS) (see ‘Catastrophic APS’ above).
The best data on morbidity and mortality are those from an international retrospective study of 1000 patients who were seen during the period 1999 to 2004 . The demographic characteristics of this group were as follow: 82 percent were female, 98.5 percent were Caucasian, the mean age at entry was 42 years, 53 percent had primary APS (36 percent with SLE). Among these patients 77 percent received treatment; 54 percent with oral anticoagulants and 45 percent with aspirin. Of the patients enrolled, outcomes were determined in 85 percent. Morbidity and mortality were as follow:
- Recurrent thrombotic or thromboembolic events occurred in 166 patients, these included strokes (n = 23), transient ischemic attacks (n = 23), deep vein thrombosis (n = 21), pulmonary embolism (n = 21), and myocardial infarction. Patients with thromboses or thromboembolic events had been receiving treatment with oral anticoagulants with a target INR of 2-3 (n = 90), or aspirin (n = 49), or were untreated (n = 27).
- Other morbid events included seizures (n = 17), heart valve thickening or dysfunction (n = 17), microangiopathic hemolytic anemia (n = 9).
- Obstetrical outcomes in 77 women who had one or more pregnancies included: live births (n = 63), preeclampsia or eclampsia (n = 8), early pregnancy loss (n = 18), premature birth (n = 28), and intrauterine growth retardation (n = 11).
Mortality in this cohort was 5.3 percent. Causes of death included (in order of frequency): bacterial infection (n = 11), myocardial infarction (n = 10), stroke (n = 7), hemorrhage (n = 6), malignancy (n = 6), CAPS (n = 5), and pulmonary embolism (n = 6).
In summary, patients who survive the initial episode that leads to the diagnosis of APS remain at risk for recurrent events. Currently available treatments (oral anticoagulation or aspirin) may reduce, but do not eliminate the risk of recurrent thrombotic, thromboembolic, or obstetrical adverse outcomes, and sometimes these events are fatal.
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Beyond the Basics topics (see “Patient information: The antiphospholipid syndrome” and “Patient information: Warfarin (Coumadin®)”)
SUMMARY AND RECOMMENDATIONS
Current therapies for the APS include the following medications (see ‘Current therapies’ above):
- Low molecular weight heparin
- Unfractionated heparin
- Antiplatelet agents
Initial approach to thrombosis — The initial approach to thrombosis in the APS is identical to that of many other thromboses. For acute thrombotic events in patients with aPL, the first therapy is heparin. We recommend low molecular weight (LMW) heparin for most APS-associated thrombotic events (Grade 1B). (See “Treatment of lower extremity deep vein thrombosis” and ‘Warfarin’ above.)
The pregnant patient — Heparin also plays a critical role in the treatment of the pregnant patient with the APS, because warfarin is contraindicated in pregnancy. Treatment of the pregnant APS patient is reviewed separately. (See “Management of pregnant women with antiphospholipid antibodies or the antiphospholipid syndrome”, section on ‘Heparin/heparin with aspirin’.)
Chronic management — As with other thromboses, patients should be transitioned from heparin to warfarin. We recommend an INR range between 2.0 and 3.0 rather than more intensive anticoagulation (Grade 1A). (See ‘Intensity of anticoagulation’ above.)
Duration of chronic therapy — The optimal duration of anticoagulation for venous thromboembolic disease following a first event is uncertain. However, given the high likelihood of recurrence in the untreated patient and the potentially devastating nature of recurrent thromboembolic events, we recommend lifelong anticoagulation for patients with the APS (Grade 1B). (See ‘Duration of warfarin use’ above.)
Prophylaxis of the asymptomatic patient — In the absence of symptoms or a history of symptoms attributable to the APS, we do not recommend the use of aspirin as prophylaxis (Grade 2B). For patients with SLE and aPL but no APS manifestations, the combination of low-dose aspirin and hydroxychloroquine may be considered (Grade 2C). (See ‘Prophylaxis’ above.)
- Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:204S.
- Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688.
- Segal JB, Streiff MB, Hofmann LV, et al. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med 2007; 146:211.
- Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996; 334:682.
- Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334:677.
- Boccalon H, Elias A, Chalé JJ, et al. Clinical outcome and cost of hospital vs home treatment of proximal deep vein thrombosis with a low-molecular-weight heparin: the Vascular Midi-Pyrenees study. Arch Intern Med 2000; 160:1769.
- O’Shaughnessy D, Miles J, Wimperis J. UK patients with deep-vein thrombosis can be safely treated as out-patients. QJM 2000; 93:663.
- Grau E, Tenias JM, Real E, et al. Home treatment of deep venous thrombosis with low molecular weight heparin: Long-term incidence of recurrent venous thromboembolism. Am J Hematol 2001; 67:10.
- Dunn A, Bioh D, Beran M, et al. Effect of intravenous heparin administration on duration of hospitalization. Mayo Clin Proc 2004; 79:159.
- Douketis JD. Treatment of deep vein thrombosis: what factors determine appropriate treatment? Can Fam Physician 2005; 51:217.
- Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349:1133.
- Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005; 3:848.
- Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117:303.
- Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332:993.
- Erkan D, Yazici Y, Peterson MG, et al. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 2002; 41:924.
- Thai KE, Barrett W, Kossard S. Reactive angioendotheliomatosis in the setting of antiphospholipid syndrome. Australas J Dermatol 2003; 44:151.
- Bick RL. Antiphospholipid thrombosis syndromes. Clin Appl Thromb Hemost 2001; 7:241.
- Edwards MH, Pierangeli S, Liu X, et al. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 1997; 96:4380.
- Espinola RG, Pierangeli SS, Gharavi AE, et al. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost 2002; 87:518.
- Lockshin M, Tenedios F, Petri M, et al. Cardiac disease in the antiphospholipid syndrome: recommendations for treatment. Committee consensus report. Lupus 2003; 12:518.
- Vianna JL, Khamashta MA, Ordi-Ros J, et al. Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients. Am J Med 1994; 96:3.
- Hereng T, Lambert M, Hachulla E, et al. Influence of aspirin on the clinical outcomes of 103 anti-phospholipid antibodies-positive patients. Lupus 2008; 17:11.
- Erkan D, Harrison MJ, Levy R, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum 2007; 56:2382.
- Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum 2009; 61:29.
- Ruffatti A, Del Ross T, Ciprian M, et al. Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study. Ann Rheum Dis 2009; 68:397.
- Shah NM, Khamashta MA, Atsumi T, Hughes GR. Outcome of patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Lupus 1998; 7:3.
- Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheumatol 2002; 29:2531.
- Escalante A, Brey RL, Mitchell BD Jr, Dreiner U. Accuracy of anticardiolipin antibodies in identifying a history of thrombosis among patients with systemic lupus erythematosus. Am J Med 1995; 98:559.
- Alarcón-Segovia D, Boffa MC, Branch W, et al. Prophylaxis of the antiphospholipid syndrome: a consensus report. Lupus 2003; 12:499.
- Erkan D, Merrill JT, Yazici Y, et al. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum 2001; 44:1466.
- Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: do the benefits outweigh the risks? A decision analysis. Arch Intern Med 2000; 160:2042.
- Ruiz-Irastorza G, Khamashta MA. The treatment of antiphospholipid syndrome: a harmonic contrast. Best Pract Res Clin Rheumatol 2007; 21:1079.
- Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum 2007; 57:1487.
- Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998; 104:332.
- Erkan D, Leibowitz E, Berman J, Lockshin MD. Perioperative medical management of antiphospholipid syndrome: hospital for special surgery experience, review of literature, and recommendations. J Rheumatol 2002; 29:843.
- Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke 2006; 37:577.
- Muscal E, Brey RL. Neurologic manifestations of the antiphospholipid syndrome: integrating molecular and clinical lessons. Curr Rheumatol Rep 2008; 10:67.
- Zavaleta NE, Montes RM, Soto ME, et al. Primary antiphospholipid syndrome: a 5-year transesophageal echocardiographic followup study. J Rheumatol 2004; 31:2402.
- Atsumi T, Furukawa S, Amengual O, Koike T. Antiphospholipid antibody associated thrombocytopenia and the paradoxical risk of thrombosis. Lupus 2005; 14:499.
- Leuzzi RA, Davis GH, Cowchock FS, et al. Management of immune thrombocytopenic purpura associated with the antiphospholipid antibody syndrome. Clin Exp Rheumatol 1997; 15:197.
- Petri M. Pathogenesis and treatment of the antiphospholipid antibody syndrome. Med Clin North Am 1997; 81:151.
- Kavanaugh A. Danazol therapy in thrombocytopenia associated with the antiphospholipid antibody syndrome. Ann Intern Med 1994; 121:767.
- Alarcón-Segovia D, Sánchez-Guerrero J. Correction of thrombocytopenia with small dose aspirin in the primary antiphospholipid syndrome. J Rheumatol 1989; 16:1359.
- Durand JM, Lefevre P, Kaplanski G, et al. Correction of thrombocytopenia with dapsone in the primary antiphospholipid syndrome. J Rheumatol 1993; 20:1777.
- Suarez IM, Diaz RA, Aguayo Canela D, Pujol de la Llave E. Correction of severe thrombocytopenia with chloroquine in the primary antiphospholipid syndrome. Lupus 1996; 5:81.
- Erkan D, Cervera R, Asherson RA. Catastrophic antiphospholipid syndrome: where do we stand? Arthritis Rheum 2003; 48:3320.
- Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore) 1998; 77:195.
- Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum 2006; 54:2568.
- Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001; 80:355.
- Erkan D, Asherson RA, Espinosa G, et al. Long term outcome of catastrophic antiphospholipid syndrome survivors. Ann Rheum Dis 2003; 62:530.
- Lockshin MD, Erkan D. Treatment of the antiphospholipid syndrome. N Engl J Med 2003; 349:1177.
- Szczepiorkowski ZM, Bandarenko N, Kim HC, et al. Guidelines on the use of therapeutic apheresis in clinical practice: evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2007; 22:106.
- Zar T, Kaplan AA. Predictable removal of anticardiolipin antibody by therapeutic plasma exchange (TPE) in catastrophic antiphospholipid antibody syndrome (CAPS). Clin Nephrol 2008; 70:77.
- Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997; 127:177.
- Hylek EM, Heiman H, Skates SJ, et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279:657.
- Robert A, Le Querrec A, Delahousse B, et al. Control of oral anticoagulation in patients with the antiphospholipid syndrome–influence of the lupus anticoagulant on International Normalized Ratio. Groupe Méthodologie en Hémostase du Groupe d’Etudes sur l’Hémostases et la Thrombose. Thromb Haemost 1998; 80:99.
- Kasthuri RS, Roubey RA. Warfarin and the antiphospholipid syndrome: does one size fit all? Arthritis Rheum 2007; 57:1346.
- Lawrie AS, Purdy G, Mackie IJ, Machin SJ. Monitoring of oral anticoagulant therapy in lupus anticoagulant positive patients with the anti-phospholipid syndrome. Br J Haematol 1997; 98:887.
- Douketis JD, Crowther MA, Julian JA, et al. The effects of low-intensity warfarin on coagulation activation in patients with antiphospholipid antibodies and systemic lupus erythematosus. Thromb Haemost 1999; 82:1028.
- Tripodi A, Chantarangkul V, Clerici M, et al. Laboratory control of oral anticoagulant treatment by the INR system in patients with the antiphospholipid syndrome and lupus anticoagulant. Results of a collaborative study involving nine commercial thromboplastins. Br J Haematol 2001; 115:672.
- Lockshin MD. Antiphospholipid antibody. Babies, blood clots, biology. JAMA 1997; 277:1549.
- Ruiz-Irastorza G, Khamashta MA, Hunt BJ, et al. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med 2002; 162:1164.
- Statkute L, Traynor A, Oyama Y, et al. Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation. Blood 2005; 106:2700.
- Kumar, D, Roubey, RA. Use of rituximab in the antiphospholipid syndrome. Curr Rheumatol Rep 2010; :.
- Cervera R, Khamashta MA, Shoenfeld Y, et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2009; 68:1428.