Hematology

Clinical manifestations of the antiphospholipid syndrome

Clinical manifestations of the antiphospholipid syndrome:

INTRODUCTION — The antiphospholipid syndrome (APS) is defined by two major components (see ‘Classification criteria’ below):

 

  • The occurrence of at least one clinical feature: vascular event or pregnancy morbidity AND
  • The presence of at least one type of autoantibody known as an antiphospholipid antibody (aPL) on two separate occasions at least 12 weeks apart.

 

In addition, there are aPL-related clinical manifestations that are not part of the APS Classification Criteria, such as livedo reticularis, thrombocytopenia, cardiac valve disease, and aPL-nephropathy.

Although the clinical manifestations of APS occur in other disease populations, in the APS they occur in the context of aPL. APL are directed against serum proteins bound to anionic phospholipids and may be detected by:

 

  • Lupus anticoagulant tests
  • Anticardiolipin antibody ELISA
  • Anti-ß2 glycoprotein-I ELISA

 

The full clinical significance of other antiphospholipid antibodies, including those directed against prothrombin, annexin V, phosphatidylserine, and phosphatidylinositol, remains unclear.

APS occurs as a primary condition or in the setting of an underlying systemic autoimmune disease, particularly systemic lupus erythematosus (SLE).

The clinical manifestations of the APS will be reviewed here. The pathogenesis, diagnosis, and treatment of this disorder are presented separately. (See “Pathogenesis of the antiphospholipid syndrome” and “Diagnosis of the antiphospholipid syndrome” and “Treatment of the antiphospholipid syndrome”.)

THE ANTIBODIES — The different aPL and their serologic assays are discussed in detail separately. (See “Diagnosis of the antiphospholipid syndrome” and “Pathogenesis of the antiphospholipid syndrome”.)

As background to a discussion of the clinical manifestations of the APS, we will summarize briefly the relationships between the three major aPL, one or more of which is present in patients with APS:

 

  • Anticardiolipin antibodies (aCL)
  • Antibodies to ß2-glycoprotein-I (ß2-GP-I)
  • Lupus anticoagulant (LA)

 

ACL and ß2-GP-I assays — APL binding to phospholipids is mediated through nonimmunoglobulin phospholipid-binding plasma proteins. ß2-GP-I is the main antigenic target of aPL. Some experienced clinical laboratories can distinguish between:

 

  • Antibodies to cardiolipin and other phospholipids.
  • Antibodies to cardiolipin that require the presence of ß2-GP-I for binding and those that do not. However, such assays are not generally commercially available.
  • Antibodies binding to ß2-GP-I that are independent of the presence of phospholipids, and those for which phospholipids are required

 

Antibody levels for aCL of IgG and IgM type are reported in units as GPL and MPL, respectively. Recommendations for a standard approach to testing and reporting were published in 2001 [1]. (See “Pathogenesis of the antiphospholipid syndrome”, section on ‘Antiphospholipid antibodies’.)

ß2-GP-I is the most common target of aPL. This protein, also known as apolipoprotein H, becomes antigenic upon binding to a negatively-charged surface. The relevance of this feature is that positive aCL ELISAs with clinical features of APS are usually caused by the binding of anti-ß2-GP-I antibodies. Patients who have positive aCL by ELISA but negative assays for anti-ß2-GP-I antibodies may be at a substantially lower or no increased risk for clotting, but additional work in this area is required.

Prior to the development of the aCL assay, it was recognized that patients with a history of a false positive test for syphilis might have a positive lupus anticoagulant (LA) test and symptoms of what became known as the APS. A false positive test for syphilis used to be part of the criteria for the diagnosis of SLE, but has now been replaced by the three tests for APL (ie, ACL, antiβ2-GP-I, and LA).

Lupus anticoagulant — The lupus anticoagulant phenomenon refers to the ability of aPL to cause prolongation of in vitro clotting assays such as the activated partial thromboplastin time (aPTT), the dilute Russell viper venom time (dRVVT), the kaolin clotting time or, infrequently, the prothrombin time. This prolongation is not reversed when the patient’s plasma is diluted 1:1 with normal platelet-free plasma. In contrast, such mixing studies would correct the clotting abnormality associated with factor deficiencies. Thus, the term “the lupus anticoagulant” is a misnomer; it is generally associated with a clotting tendency rather than an anticoagulant effect.

One common effect of aPL detected by routine laboratory testing is the prolongation of the aPTT. However, only about one-half of patients with LAs have prolongations of the aPTT. Thus, if APS is suspected strongly, additional testing, usually with a dRVVT, is essential.

Laboratory experience is important in LA assays. In one study, one quarter of all plasma samples diagnosed as having LA activity were found to be false-positive tests upon measurement in a reference laboratory [2]. Guidelines for the detection of Las are described in detail elsewhere. (See “Diagnosis of the antiphospholipid syndrome”, section on ‘Lupus anticoagulant’ and “Diagnosis of the antiphospholipid syndrome”, section on ‘Detection of LA during anticoagulation’.)

Other antiphospholipid antibodies — Antibodies to prothrombin, annexin V, phosphatidylserine, and other proteins have also been associated with the APS. However, understanding of the potential roles played by such antibodies in the APS is incomplete, and assays for these antibodies are not part of the standard evaluation when the APS is suspected. Antibodies to prothrombin are associated with bleeding as well as thrombosis. (See ‘Bleeding episodes’ below.)

In one study of 101 patients with SLE, the presence of IgG antibodies to prothrombin was associated with thrombosis [3]. Furthermore, the presence of LA, aCL antibodies, anti-ß2-GP-I antibodies, and anti-prothrombin antibodies conferred a thirty-fold increased risk for thrombosis.

In summary, the basic science behind the APS is an evolving field. Assays for aPL continue to undergo processes of discovery and refinement. For clinical purposes now, three types of aPL tests are usually performed when the APS is suspected: the LA test, the aCL ELISA, and the anti-ß2-GP-I ELISA.

OTHER ASSOCIATIONS — Various aPL may be present in some people who are otherwise healthy, have autoimmune or rheumatic disease, have been exposed to certain drugs or infectious agents. These and other associations are discussed in more detail elsewhere. (See “Pathogenesis of the antiphospholipid syndrome”, section on ‘Prevalence in different conditions’.)

CLASSIFICATION CRITERIA — Classification criteria have been developed for research purposes. They may be helpful to clinicians, but not all the classification criteria need to be met to make a clinical diagnosis of APS. (See “Diagnosis of the antiphospholipid syndrome”.)

International consensus conferences have proposed [4] and revised [5] classification criteria for definite APS. Definite APS is considered present if at least one of the following clinical criteria and at least one of the following laboratory criteria are satisfied.

 

  • Clinical — One or more episodes of venous, arterial, or small vessel thrombosis and/or morbidity with pregnancy.

 

 

  • Thrombosis — Unequivocal imaging or histologic evidence of thrombosis in any tissue or organ, OR
  • Pregnancy morbidity — Otherwise unexplained death at ≥10 weeks gestation of a morphologically normal fetus, OR
  • One or more premature births before 34 weeks of gestation because of eclampsia, preeclampsia, or placental insufficiency, OR
  • Three or more embryonic (<10 week gestation) pregnancy losses unexplained by maternal or paternal chromosomal abnormalities or maternal anatomic or hormonal causes.

 

 

  • Laboratory — The presence of aPL, on two or more occasions at least 12 weeks apart and no more than five years prior to clinical manifestations, as demonstrated by one or more of the following:

 

 

  • IgG and/or IgM aCL in moderate or high titer (>40 units GPL or MPL or > 99th percentile for the testing laboratory)

 

 

  • Antibodies to ß2-GP-I of IgG or IgM isotype at a titer >99th percentile for the testing laboratory when tested according to recommended procedures [6].
  • LA activity detected according to published guidelines [7,8].

 

PATHOLOGY — The characteristic pathologic finding in the APS is a bland thrombosis with minimal vascular or perivascular inflammation (picture 1). This change is not specific for the APS, as it also occurs in a variety of other disorders including the hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura, systemic sclerosis (scleroderma), and malignant hypertension. Larger vessels, both arteries and veins, may develop in situ thrombosis or be sites from or into which emboli originate or lodge.

CLINICAL MANIFESTATIONS — The APS is characterized by venous or arterial thromboses, morbidity occurring in the setting of pregnancy, and/or aPL-related clinical manifestations that are not part of the APS Classification Criteria, such as livedo reticularis, thrombocytopenia, cardiac valve disease, or aPL-nephropathy [9].

In a series of 1000 patients with either primary or secondary APS, the various disease features were [10]:

 

  • Deep vein thrombosis — 32 percent
  • Thrombocytopenia — 22 percent
  • Livedo reticularis — 20 percent
  • Stroke — 13 percent
  • Superficial thrombophlebitis — 9 percent
  • Pulmonary embolism — 9 percent
  • Fetal loss — 8 percent
  • Transient ischemic attack — 7 percent
  • Hemolytic anemia — 7 percent

 

In rare patients, APS results in multiorgan failure because of multiple blood vessel occlusions, a condition referred to as “catastrophic antiphospholipid syndrome” [11]. (See ‘Catastrophic APS’ below.)

In addition to those already mentioned above, other possible aPL-related clinical manifestations include migraine headache, Raynaud phenomenon, pulmonary hypertension, avascular necrosis, cutaneous ulcers that resemble pyoderma gangrenosum, adrenal insufficiency due to hemorrhagic infarction, and cognitive deficits [9,10,12-23]. For some of these clinical entities, the true relationship between the occurrence of the condition and the presence of aPL is not clear.

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Thrombosis — The risk of both venous and arterial thrombosis and/or thromboembolism is increased in individuals with positive tests for LA activity (odds ratio [OR] of 11) or medium or high levels of aCL (OR 1.6) [24]. The risk of recurrent thrombosis or thromboembolism may be further enhanced in those with positivity to three aPL activities (LA, aCL, and ß2-glycoprotein-I) upon repeated testing [25].

Initial site — Venous thromboses are more common than arterial thromboses in the APS [14,26]. The most common site of deep vein thrombosis (DVT) is the calf, but the renal veins, the hepatic, axillary, subclavian, and retinal veins, the cerebral sinuses, and the vena cavae may also be involved. The most common site of arterial thrombosis is the cerebral vessels, but coronary, renal, and mesenteric arteries and arterial bypass graft occlusions have also been noted.

To some degree, the site of thrombosis may be related to the type of aPL present. This was illustrated in a retrospective study of 637 patients with APS in which DVT and PE were more frequent among patients with LA, while coronary, cerebrovascular, and peripheral arterial events were more likely in those with elevated levels of IgG or IgM aCL.

Deep venous thrombosis — APL can be detected in approximately 5 to 21 percent of all patients with DVT [26,27]. The incidence of DVT may correlate with the level of aCL. As an example, one study found that DVT occurred in 44 percent of patients with high titers of aCL, in 29 percent with low titers, and in only 10 percent of those without these antibodies [28].

 

  • Risk in asymptomatic persons — There are conflicting data regarding the question of whether the presence of elevated levels of aCL in otherwise healthy individuals is associated with an increased risk of DVT or PE. Two well designed prospective case-controlled studies of aCL and venous thrombosis came to different conclusions:
  • In a study of 22,071 male physicians, 90 cases of DVT and/or PE were matched with 90 controls. An aCL level greater than the 95th percentile for the entire group (≥33 GPL) was associated with a relative risk for DVT of 5.3 [29].
  • In contrast, in a subsequent study of 21,680 initially healthy men and women, 317 cases of DVT and/or PE were compared to 655 controls [30]. No significant difference in the risk of DVT or PE was noted for subjects with elevated IgG aCL levels (≥95th percentile) or elevated IgM aCL (≥ 28.7 MPL).

 

A meta-analysis of six studies that included the first but not the second study found an overall odds ratio for venous thromboembolism of 1.56 for aCL (95 percent CI 1.1 to 2.2) [31]. The odds ratio was substantially higher in the presence of LA activity (11.1; 95 percent CI 3.8 to 32.3).

As noted above, one possible determinant of the pathogenicity of aCL is whether or not antibodies to ß2-GP-I are present simultaneously (see ‘The antibodies’ above).

Stroke — The APS is strongly linked to ischemic stroke [32]. The occurrence of livedo reticularis in association with a stroke is known as Sneddon’s syndrome [33]. In the great majority of cases, Sneddon’s syndrome is associated with detectable aPL.

A thrombotic stroke occurring in a young patient with no overt risk factors for cerebrovascular disease is the classic setting in which to suspect the APS. In one study, aPL were found in 25 percent of patients younger than 45 years of age who presented with a stroke of unclear etiology [34]. In another report, 20 percent of stroke victims under the age of 50 had aPL [26].

Ischemic stroke may be a manifestation in situ thrombosis or due to embolism arising from valvular heart disease. If routine transthoracic echocardiography is normal, transesophageal echocardiography may be indicated to assess for vegetations due to nonbacterial endocarditis (see ‘Valvular disease’ below).

Several studies have evaluated the risk of stroke associated with the presence of aPL:

 

  • In a review of 2000 healthy male subjects, the relative risk of stroke at 15 years of follow-up was 2.2 in subjects with aPL [35]. Events were observed primarily in subjects who had both ß2-GP-I and IgG aCL (ie, ß2-GP-I dependent aCL).
  • In the Stroke Prevention in Young Women study, the presence of LAs and aCL was evaluated in 160 cases and 340 controls [36]. After adjustment for potential confounders, the relative odds of stroke for women with an aCL of any isotype or an LA was 1.87 (95% CI 1.2 to 2.8). Similar findings of an increased risk of ischemic stroke associated with aCL limited to women were noted in a report from the Framingham Cohort and Offspring Study (hazard ratio for women 2.6; 95% CI 1.3 to 5.4) [37].

 

Neurologic syndromes besides stroke — Strong associations are now recognized between the presence of aPL and the occurrence of cognitive deficits and/or white matter lesions [32,38]. However, the link with the APS is less strong for other neurological associations.

Cognitive deficits — Considerable interest (and controversy) has focused on the relationship between aPL and cognitive deficits. The degree of reported cognitive deficits ranges from subtle findings to transient global amnesia to permanent and profound cognitive functioning. The cognitive deficits reported in the APS are sometimes but not always associated with white matter lesions.

Cognitive deficits were demonstrated in a study of 60 patients with primary or secondary APS who underwent comprehensive neuropsychological testing [22]. The APS patients were compared with 60 healthy controls matched for age, sex, and education, and 25 disease controls (SLE and rheumatoid arthritis patients who did not have APS). The following observations were made:

 

  • Cognitive deficits were significantly more frequent in the patients with APS (42 versus 18 and 16 percent of the healthy and disease controls, respectively).
  • Cognitive dysfunction in the APS patients was associated with the presence of livedo reticularis on physical examination and the finding of white matter lesions on brain MRI.
  • No relationship was detected between cognitive dysfunction and previous central nervous system disease (eg, stroke).

 

White matter lesions — Central nervous system involvement in APS is associated with high-intensity lesions on MRI that are suggestive of a vasculopathy [39]. These lesions may be difficult to distinguish from those in multiple sclerosis [40,41]. When present in patients with clinical or serologic features of SLE or APS, these lesions have been referred to as “lupoid sclerosis” [42,43]. (See “Neurologic manifestations of systemic lupus erythematosus”, section on ‘Cranial neuropathies’.)

A number of patients with multiple sclerosis also have aPL. However, there appears to be no correlation between these antibodies and any clinical features of multiple sclerosis [44].

Other neurological associations — Other neurologic disorders with which aPL have been reported include [9,10,22,45-54]:

 

  • Epilepsy
  • Depression
  • Psychosis
  • Chorea and hemiballismus
  • Transverse myelopathy
  • Sensorineural hearing loss
  • Orthostatic hypotension
  • Migraine

 

The strength of association for many of these conditions is weak.

Recurrent thrombotic events — Recurrent thrombotic events are common in APS. Most but not all observers have noted that an initial arterial thrombosis tends to be followed by an arterial event, and that an initial venous thrombosis is usually followed by a venous event [55-57]. In a report in which 186 recurrences occurred in 101 patients, an initial arterial thrombosis was followed by an arterial thrombosis in 93 percent, while an initial venous thrombosis was followed by a venous thrombosis in 76 percent [57]. The factors that determine the predilection for the venous or arterial circulation are not known.

The recurrence rate of thrombotic events among patients with APS is variable [56,58-60] and the presence of aCL is a risk factor for recurrence [56,58-60]. The largest experience comes from a prospective study of 412 patients presenting with a first episode of venous thromboembolism who were treated with six months of anticoagulation with warfarin [59]. The following findings were noted:

 

  • The risk of recurrence within the first six months after stopping anticoagulation was twice as high among patients with aCL compared to those without such antibodies (29 percent versus 14 percent). In addition, the risk of recurrence increased with the aCL titer.
  • Among 34 patients with a second venous thromboembolic event and aCL, there were no recurrences during the second course of anticoagulant therapy versus 20 percent in those who were retreated for only six months.
  • Four year mortality was significantly higher in the patients with aCL (15 versus 6 percent in those without aCL).

 

The prognostic importance of aCL was noted in another cohort of 56 patients with primary APS who were followed for five years [60]. Fifteen patients (27 percent) had at least one recurrent event. On multivariate analysis, only an aCL level >40 GPL units was an independent predictor of recurrent thromboembolic events.

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Pregnancy loss and preeclampsia — The presence of APS may be related to several types of morbidity during pregnancy. These include fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, or multiple embryonic losses (<10 weeks gestation). Fetal loss in patients with aPL and the approach to women with recurrent fetal loss are presented separately. (See “Obstetrical manifestations of the antiphospholipid syndrome” and “Evaluation of couples with recurrent pregnancy loss”.)

In patients with preeclampsia or the HELLP syndrome, the possibility of the catastrophic APS must be considered, particularly in patients with histories of thrombosis or spontaneous abortions [61]. (See ‘Catastrophic APS’ below.)

Hematologic manifestations — Prominent hematologic manifestations of APS include thrombocytopenia, microangiopathic hemolytic anemia and, in rare cases, bleeding.

Thrombocytopenia — Thrombocytopenia is among the most common clinical manifestations of the APS [10]. The platelet count is usually in the range of 50,000 to 140,000/microL. Thrombocytopenia does not preclude the occurrence of thrombotic complications of APS.

A review of 13 studies of 869 patients with SLE (and/or SLE-like diseases) found that thrombocytopenia was more common in those with LA (55 percent) and aCL (29 percent) than in those without these antibodies [62]. Conversely, patients with thrombocytopenia associated with autoimmune disorders frequently have aPL (eg, 70 to 82 percent of patients with SLE and thrombocytopenia, and 30 to 40 percent of those with idiopathic thrombocytopenic purpura (ITP)) [10,62-64].

The risk of developing thrombotic events or fetal loss is increased in patients with ITP who have aPL. This was illustrated in a prospective study of 82 patients presenting with ITP [64]. The rate of thrombotic events or fetal loss at five years was approximately 60 percent in the 31 patients (38 percent) with aPL had thrombotic events compared to a 2 to 4 percent in those who did not have aPL. Patients with ITP and the persistent presence of a LA appeared to be at highest risk; nearly half of such patients developed thrombotic events during a mean of 38 months of follow-up. (See “Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults”.)

Thrombotic microangiopathy — APL have been implicated in some cases of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS) that occur in SLE. In one report, for example, five of eight such patients had aPL [65]. In addition, some patients with primary APS develop TTP. (See “Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”, section on ‘Antiphospholipid antibodies’.)

In a review of 46 patients with thrombotic microangiopathy and aPL, the following associated clinical syndromes were noted [66]:

 

  • TTP/HUS in 33 percent.
  • Catastrophic APS in 23 percent. (See ‘Catastrophic APS’ below.)
  • Acute renal failure in 15 percent. (See “Antiphospholipid syndrome and the kidney”.)
  • Malignant hypertension in 13 percent. (See “Malignant hypertension and hypertensive encephalopathy in adults”.)
  • HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count in association with pregnancy) in 4 percent. (See “HELLP syndrome”.)

 

Some patients with APS have only manifestations of hemolysis. In a series of 1000 patients with APS, hemolytic anemia was observed in 10 percent at some time during a mean of seven years of observation [10]. However, this cohort included patients with SLE and the cause of the hemolysis was not stated. Both autoimmune hemolytic anemia and microangiopathic destruction of red cells may play a role in such patients.

Bleeding episodes — The presence of antibodies to prothrombin should be suspected when a patient with a known LA also has a low prothrombin level and develops bleeding complications rather than thrombosis [67,68]. (See “Acquired inhibitors of coagulation”, section on ‘Prothrombin inhibitors’.)

Pulmonary disease — Pulmonary embolism occurs in approximately one-third of patients with the APS who develop DVT. Other recognized pulmonary complications of the APS include [10,69-72]:

 

  • Pulmonary arterial thrombosis with or without thromboembolic pulmonary hypertension. (See “Clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension”.)
  • Alveolar hemorrhage. (See “The diffuse alveolar hemorrhage syndromes”.)

 

In addition, fibrosing alveolitis, adult respiratory distress syndrome, and nonthromboembolic pulmonary hypertension have been reported in association with aPL [69,70]. However, the relationship to these disorders to aPL is unclear

Cardiovascular disease — Patients with aPL commonly have cardiac disease, including valvular thickening, mitral valve nodules, and nonbacterial vegetations (picture 2) [10,19,71,73-76]. Involvement of the mitral and aortic valves can lead to valvular regurgitation and rarely to stenosis [74-76].

APL have also been incriminated in intracardiac thrombi, pericardial effusion, cardiomyopathy, emboli in those with or without infective endocarditis, premature restenosis of vein grafts for coronary bypass, and peripheral vascular disease [10,19,73,74,77-81].

Valvular disease — The relationship between aPL and cardiovascular manifestations of SLE was evaluated in a group of 200 patients from an SLE registry; 21 percent had either aCL or a LA [76]. The patients with aPL had higher rates of mitral valve nodules and moderate to severe mitral regurgitation (14 percent versus 4 percent without aPL). Mitral valve nodules were more common in patients with high titers of IgG aPL (31 versus 4 percent without aPL). APL were not associated with cardiac hypertrophy, systolic dysfunction, atherosclerosis, or pulmonary hypertension.

Ischemic heart disease — Whether an association exists between the APS and an increased incidence of ischemic heart disease has been controversial [35,82-84].

 

  • In different series, aCL were present in 20 percent of patients with ischemic heart disease and no other autoimmune disorder [82] and antibodies to ß2-GP-I were present in 30 percent of patients with unstable angina [84].
  • An association between angina pectoris with angiographically normal epicardial coronary arteries (cardiac syndrome X) and APS has been suggested [85].
  • Abnormalities on contrast enhanced cardiac MRI were more prevalent among patients with APS (8 of 27, 30 percent) than in healthy controls (3 of 87, 3.5 percent) [86]. These observations, if confirmed, suggest that many patients with APS are at risk for CAD.

 

 

  • A case-control study of 2000 patients found a substantial increase in the risk of myocardial infarction associated with the presence of IgG aCL directed against ß2-GP-I (adjusted odds ratio of 1.8, 95 percent CI 1.2 to 2.6) [35]. As was the case for stroke risk, aCL alone, antibodies to ß2-GP-I alone, and aPL of any immunoglobulin class other than IgG did not confer an increased risk of myocardial infarction.

 

Spontaneous echo contrast — Spontaneous echo contrast (SEC) in the left atrium, a finding that is thought to result from clumping of red blood cells in the setting of low shear stress, is a risk factor for left atrial thrombus formation and arterial embolism. SEC is present in up to 16 percent of APS patients [75], but its clinical significance in this setting is uncertain. (See “Echocardiography in detection of intracardiac sources of embolism”, section on ‘Left atrial spontaneous echo contrast’.)

Cutaneous — APL have been associated with many cutaneous abnormalities including splinter hemorrhages, livedo reticularis (picture 3), cutaneous necrosis and infarction, thrombophlebitis, digital gangrene, skin ulcerations, lesions resembling vasculitis (“pseudovasculitic” nodules, macules), and livedoid vasculopathy (atrophie blanche) [5,10,87-89]. (See “Livedoid vasculopathy”.)

A loss of normal elastic tissue known as anetoderma, which presents as localized areas of wrinkled or flaccid skin, has also been noted in patients with SLE and APS [5,90].

The occurrence of livedo reticularis in association with stroke is known as Sneddon’s syndrome [33]. In approximately 50 percent of cases, Sneddon’s syndrome is associated with detectable aPL.

In a series of 200 consecutive cases of patients with the APS (either primary APS or APS secondary to SLE), 49 percent of patients had cutaneous findings associated with their disease. In 31 percent of cases, the cutaneous lesions were evident at presentation. The following frequency of lesions was observed [88]:

 

  • Livedo reticularis — 26 percent
  • Digital necrosis — 8 percent
  • Splinter hemorrhages — 5 percent
  • Superficial venous thrombosis — 5 percent
  • Post-phlebitic ulcers — 5 percent
  • Circumscribed cutaneous necrosis — 4 percent
  • Thrombocytopenic purpura — 4 percent
  • Pseudovasculitis — 3 percent
  • Extensive cutaneous necrosis — 2 percent
  • Anetoderma — 2 percent

 

Livedo reticularis — Livedo reticularis is associated with arterial lesions and multiple thromboses in the APS [91]. In the review of 200 patients, livedo reticularis was associated with cerebral or ocular ischemic events (odds ratio 10.8) [88]. In contrast, livedo reticularis was observed with decreased frequency in patients who experienced only venous thromboses (odds ratio 0.2).

There is considerable ambiguity in the literature with regard to the terms “livedo reticularis” and “livedo racemosa” [92]. Livedo racemosa is characterized by a violaceous net-like pattern on the skin with irregular and/or broken circles; livedo reticularis is characterized by unbroken circles [93]. Livedo racemosa, named by Ehrmann in 1907 [94], is a more striking cutaneous finding than livedo reticularis [92]. In addition, livedo reticularis often occurs in physiologic settings rather than disease states [95].

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The clinical significance of differentiating between livedo racemosa and livedo reticularis was illustrated in a study of 111 patients with livedo racemosa and 32 patients with livedo reticularis [93]. The former were more likely to have biopsy-proven cutaneous vasculitis, to be younger, male, have arthralgia, higher levels of CRP, and antibodies to phosphatidylserine prothrombin complexes.

Renal disease — Thrombotic renal disease occur in a minority of patients with APS. Glomerular capillaries and other renal vessels, both arteries and veins of all sizes, can be affected. The disease may be silent or produce acute or chronic renal failure with proteinuria. A detailed discussion of kidney disease associated with aPL is presented elsewhere. (See “Antiphospholipid syndrome and the kidney”.)

Gastrointestinal disease — Patients with aPL may have ischemia involving the esophagus, stomach, duodenum, jejunum, ileum, or colon resulting in gastrointestinal bleeding, abdominal pain, an acute abdomen, esophageal necrosis with perforation, or giant gastric or atypical duodenal ulceration [96]. Splenic or pancreatic infarction may also occur [10]. In addition, the liver may involved; hepatic or portal venous thrombosis may result in the Budd-Chiari syndrome, hepatic-veno-occlusive disease, hepatic infarction, portal hypertension, and cirrhosis. [96].

Ocular manifestations — Amaurosis fugax, retinal venous and arterial occlusion, and anterior ischemic optic neuropathy have occurred in patients with aPL [10,97]. The presence of such antibodies may is a risk factor for occlusive vascular disorders of the eye. This was illustrated in a case-control study of 68 patients with such occlusive disorders and 94 controls (45 with inflammatory eye diseases and 49 healthy subjects) [98]. ACL or LA activity was present in 24 percent of those with occlusive vascular eye disease, compared with only 9 percent and 8 percent of those with inflammatory eye disease and healthy controls, respectively.

Adrenal disease — The development of abdominal pain and weakness may be the result of adrenal insufficiency. Loss of adrenal function is most often due to adrenal hemorrhage and less frequently to bilateral adrenal infarction [99]. An enlarged adrenal or an adjacent mass may be apparent on a CT scan, but MRI is more effective in determining the age of adrenal hemorrhage and differentiating bleeding from other causes of adrenal gland enlargement. (See “Causes of primary adrenal insufficiency (Addison’s disease)”, section on ‘Hemorrhagic infarction’.)

Osteonecrosis — Asymptomatic changes in the appearance of the femoral heads of patients with primary APS have been noted on MRI. These findings have been interpreted to indicate osteonecrosis. However, of the 30 patients who were the subject of one report, none had changes on plain radiographs and none had progressive changes on subsequent MRIs [100]. Thus, the true nature of the association between osteonecrosis and the presence of aPL is not clear. (See “Osteonecrosis (avascular necrosis of bone)”, section on ‘Lupus’.)

Catastrophic APS — A small subset of patients with APS has widespread thrombotic disease with multiorgan failure, which is called “catastrophic APS.” Preliminary criteria proposed for classification purposes have previously been published and validated (table 1). Additional diagnostic algorithms have been proposed to facilitate early recognition of catastrophic APS [101]. The important steps in the proposed algorithms include:

 

  • History of APS and/or APL
  • Three or more new organ thromboses within a week
  • Biopsy confirmation of a microthrombus
  • Exclusion of other causes of multiple organ thromboses or microthromboses

 

Among 1000 patients with the APS followed for a mean of seven years, only 8 (0.8 percent) developed catastrophic APS [10]. In the majority of these patients, multiorgan involvement was present at the time of diagnosis of APS.

Patients with catastrophic APS may have laboratory features such as elevated fibrin degradation products, depressed fibrinogen levels, or elevated D-dimer concentrations that are more typically found with disseminated intravascular coagulation (DIC).

Catastrophic APS is frequently fatal, with a reported mortality rate approaching 50 percent despite anticoagulant and immunosuppressive treatment [99]. The treatment of the catastrophic APS is presented elsewhere (see “Treatment of the antiphospholipid syndrome”, section on ‘Catastrophic APS’).

Primary APS versus SLE — Some data suggest that the clinical manifestations of primary APS and APS associated with SLE are similar [102]. In contrast, a subsequent study of 122 patients noted that the frequency of arterial thromboses, venous thromboses, and fetal loss was greater in patients with APS and SLE than in those with primary APS [103].

A separate issue is the frequency of evolution of APS into SLE or lupus-like disease. Three studies involving 70 to 128 patients with APS found a variable rate of development of SLE over time:

 

  • 0 percent at five years [12]
  • 4 percent at 6.5 years [104]
  • 13 percent at nine years [105]

 

MORTALITY — The presence of aPL in the serum of patients with SLE has been identified as an independent risk factor for premature death. This was illustrated in an observational study of 667 patients with SLE, 49 of whom died [106]. There was an increased risk of premature death in patients with aPL, thrombocytopenia, and arterial occlusion. Other factors associated with premature death were the intensity of anticoagulation treatment, renal involvement, pleuritis, and disease activity.

Although some of the risk of early death is due to the increased propensity to thromboembolic disease, in some settings the presence of aPL may be a marker for a higher mortality rate that is not due to thrombophilia per se. As an example, in a study of 300 consecutive patients with a first ischemic stroke, stroke victims with elevated levels of aPL (IgG ACL >20 U) had a higher mortality rate during approximately two years of follow up than those with lower or absent ACL levels (33 versus 18 percent mortality, relative risk, 1.94, 95 percent CI, 1.05 to 3.67) [107]. However, the increased mortality was not due to recurrent stroke, but was associated with other characteristics of those with aPL, including a higher rate of malignancy and more prevalent risk factors for coronary heart disease.

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 information: The antiphospholipid syndrome”)

 

SUMMARY

The antiphospholipid syndrome (APS) is defined by two major components (see ‘Classification criteria’ above):

 

  • The occurrence of at least one clinical feature: vascular event or pregnancy morbidity AND
  • The presence of at least one type of autoantibody known as an antiphospholipid antibody (aPL) on two separate occasions at least 12 weeks apart.

 

In addition, there are aPL-related clinical manifestations that are not part of the APS Classification Criteria, such as livedo reticularis, thrombocytopenia, cardiac valve disease, or aPL-nephropathy.

APS occurs either as a primary condition or as a secondary condition in the setting of an underlying disease, particularly systemic lupus erythematosus (SLE). (See ‘Primary APS versus SLE’ above.)

APL are directed against serum proteins bound to anionic phospholipids and may be detected by:

 

  • Lupus anticoagulant tests
  • Anticardiolipin antibody ELISA
  • Anti-ß2 glycoprotein-I ELISA

 

(See ‘The antibodies’ above.)

Thromboses are the most common clinical manifestation of the APS. The most common sites for venous thrombosis are deep venous thromboses (and pulmonary emboli), the renal veins, the hepatic, axillary, subclavian, and retinal veins, the cerebral sinuses, and the venae cavae. (See ‘Thrombosis’ above.)

The most common site of arterial thrombosis in the APS is the brain. Ischemic stroke may also result from arterial thromboembolism. (See ‘Stroke’ above.)

Aside from strokes, a variety of other neurological syndromes have been associated with the APS, including cognitive deficits and white matter lesions. (See ‘Neurologic syndromes besides stroke’ above.)

Pregnancy manifestations of the APS include fetal death after 10 weeks gestation, premature births due to severe preeclampsia or placental insufficiency, or multiple embryonic losses (<10 weeks gestation). (See “Obstetrical manifestations of the antiphospholipid syndrome” and “Evaluation of couples with recurrent pregnancy loss”.)

In APS-associated thrombocytopenia, the platelet count is usually not severely low but rather in the range of 50,000 to 140,000/microL. Thrombosis can occur in the APS even in the presence of thrombocytopenia. (See ‘Thrombocytopenia’ above.)