Clinical manifestations

Presentation and course

Most antiphospholipid syndrome manifestations in various organs are attributed to vascular thrombosis. The organ systems involved include the following:

Neurologic. Cerebral arteries are the most common site of arterial thrombosis due to antiphospholipid antibody syndrome (49). Stroke (19.8%) and transient ischemic attacks (11.1%) were among the most common manifestations in the “Euro-Phospholipid” cohort (19). Nevertheless, in the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in 22,071 male patients, high titers and anticardiolipin IgG above the 95th percentile are associated with pulmonary embolism and venous thromboembolism but not ischemic stroke (48).

Screening for antiphospholipid antibodies is recommended in young adults (< 50 years) with ischemic stroke (53). Cerebral venous sinus thrombosis is also a well-recognized complication (25). Cerebral vascular thrombosis, embolism from large extracranial vessels, cardiac emboli from valvular vegetations, endocarditis, and intracardiac thrombi may occur.

Several neurologic conditions have been associated with antiphospholipids, including autoimmune chorea, migraine headaches, encephalopathy, seizures, dementia, Guillain-Barre syndrome, psychosis, and transverse myelopathy (21; 73; 71; 50).

Cardiac. Mural thrombosis, cardiac micro thrombi, and coronary artery disease fall within the definition of thrombotic manifestations of antiphospholipid syndrome.

Nonthrombotic endocarditis, valvular vegetations, and abnormalities (stenosis or regurgitation) have been associated with both systemic lupus erythematosus and antiphospholipid syndrome. Antiphospholipid syndrome was found in 15.5% of patients with myocardial infarction with nonobstructive coronary arteries (94). However, whether antiphospholipid syndrome is primarily causative has not been well established.

Dermatologic. Livedo reticularis and livedo vasculitis are the best described skin lesions. Others include thrombophlebitis, ulcerations, digital gangrenes, and splinter-hemorrhages. The latter are, however, not considered meritorious enough to be included as a clinical criterion.

Renal. Thrombosis of renal vein, renal artery, renal infarction, and antiphospholipid antibody nephropathy are included in this category. Antiphospholipid-associated nephropathy is a thrombotic microangiopathy involving arterioles and glomerular capillaries and may result in acute renal failure.

Chronic renal failure, acute renal failure, hematuria, and proteinuria are not considered to be directly related to antiphospholipid syndrome unless they result from the thrombotic events described above.

Pulmonary. Most common manifestations include pulmonary embolism and pulmonary arterial thrombosis. However, nonthrombotic vasculopathy and pulmonary hypertension have occasionally been reported as well.

Gastrointestinal. The commonest gastrointestinal manifestations include thrombotic events like Budd-Chiari syndrome, portal and mesenteric vein thrombosis, ischemic colitis, and splenic/hepatic/intestinal infarctions. Others include esophageal and colon perforation and cholecystitis.

Hematologic. The commonest manifestation is thrombocytopenia due to antiphospholipid splenic sequestration; however, it is rarely severe enough to lead to bleeding. Similar mechanisms lead to hemolytic anemia and acquired hypoprothrombinemia. The latter is suspected in patients with prolonged bleeding time, and these patients should have prothrombin levels tested.

Other arteriovenous manifestations. Other arteriovenous manifestations include thrombosis of aorta, axillary, ileo-femoral, and popliteal arteries. Venous thromboses are especially common as deep venous thrombosis of the leg. Other venous systems include adrenal vein and inferior venous cava.

Obstetric complications. Obstetric complications manifest as recurrent early miscarriages (prior to the tenth week of gestation), loss of a morphologically normal fetus beyond the tenth week of gestation in the absence of other maternal/fetal chromosomal abnormalities or maternal anatomic abnormalities, and placental insufficiency leading to preeclampsia and/or intrauterine growth retardation and preterm delivery. Although reported, maternal thrombocytopenia is a relatively rare manifestation of antiphospholipid syndrome.

Catastrophic antiphospholipid syndrome (CAPS). Antiphospholipid syndrome typically presents as a single event involving one organ system. Although future episodes may involve other systems, every episode is usually isolated to that system. However, less than 1% of antiphospholipid syndrome patients present with thrombosis in multiple organs, a condition defined as catastrophic antiphospholipid syndrome (CAPS). The criteria for the diagnosis of CAPS are as follows (06; 22):

• Involvement of ≥ 3 organ systems • Simultaneous onset or onset within seven days in all organ systems • Pathological evidence of thrombotic involvement of microvasculature • Presence of antiphospholipid antibodies

The clinical presentation of CAPS includes respiratory failure, stroke, renal impairment, and cutaneous manifestations and follows a fulminant course. Most often, the involved systems include renal, pulmonary, neurologic, cardiac, and cutaneous (03). Thrombosis of the microvasculature of these systems is the unifying pathological feature (07). The precipitating events are infections, surgery, or drugs. Disseminated intravascular coagulation, an unusual manifestation of isolated antiphospholipid syndrome, has been frequently associated with CAPS, probably secondary to widespread thrombotic activation.

Other presentations. Although not widely accepted, it has been proposed that antiphospholipid syndrome manifests in two other forms: pre-antiphospholipid syndrome and microangiopathic antiphospholipid syndrome (MAPS). Pre-antiphospholipid syndrome has been described as a subset associated with small vessel occlusion in at least one organ or tissue, along with involvement of two or more organs or systems (04). Pre-antiphospholipid syndrome, also referred to as “probable antiphospholipid syndrome,” is a condition thought to mimic several conditions that may presage the development of antiphospholipid syndrome, and it often presents with livedo reticularis, thrombocytopenia, fetal loss, and valve lesions in patients who often develop diagnosable antiphospholipid syndrome years later. Notwithstanding, many asymptomatic individuals with antiphospholipid and some with antiphospholipid and nonthrombotic problems never develop antiphospholipid syndrome, underscoring the tenuous relationship this supposed entity has in relation to antiphospholipid syndrome.

MAPS describes those patients with microvascular occlusions along with demonstrable antiphospholipid antibodies (04). Given the widespread thrombotic microangiopathy that characterizes MAPS, patients often exhibit severe thrombocytopenia, hemolytic anemia, thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and HELLP syndrome. Like pre-antiphospholipid syndrome, the view that MAPS represents a distinct subset of antiphospholipid syndrome has gained little currency amongst experts.

Prognosis and complications

The prognosis of antiphospholipid syndrome depends on the type of vessel and distribution of vascular territory involved. The recurrent thrombotic event is in 91% of cases in the initial vascular type (85). The risk of recurrence depends on anticoagulation and target international normalized ratio achievement, but patients with refractory antiphospholipid syndrome usually have a very grim prognosis. Screening for antiphospholipid syndrome in women of childbearing age with arterial or venous events is important because of the increased risk of fetal loss or late pregnancy complications. Lastly, it is important to have a high index of suspicion for CAPS as it can approach 50% mortality (06; 35).

There may be some correlation of higher titers of anticardiolipin antibodies to poorer outcomes and prognosis after stroke. Elevated IgM anticardiolipin antibodies have been shown to correlate to the National Institutes of Health stroke scale early after stroke, and higher IgG anticardiolipin antibody titers are correlated to disability at three months (84).

Complications in antiphospholipid syndrome are primarily associated with the primary presentation. Therefore, arterial strokes can be at higher risk of deep venous thrombosis, pulmonary embolism, or pneumonia; peripheral arterial ischemia can result in gangrene and limb loss; and coronary ischemia can result in heart failure and pulmonary edema. Venous thrombosis-like deep venous thrombosis often gets complicated by pulmonary embolism, and other syndromes like hepatic vein thrombosis can result in liver failure.

Clinical vignette

Clinical vignette 1: primary antiphospholipid syndrome. A 51-year-old woman without traditional stroke or vascular risk factors presented with sudden central scotoma in her right eye due to central retinal artery occlusion. Her workup revealed minimal atherosclerosis of her right internal carotid arteries and proximal vessels. Her transesophageal echocardiogram did not reveal any abnormality. She was tested for anticardiolipin antibody, which was strongly positive (> 99 percentile). Patient had negative lupus anticoagulant and β2 glycoprotein antibody.

Clinical vignette 2: secondary antiphospholipid syndrome. A 35-year-old woman presented to the doctor for possible seizures in her sleep. Review of her medical history revealed recurrent miscarriages. The first one, five years prior to her current presentation, occurred at 12 weeks. Her second one was a year later, at 26 weeks. Her third pregnancy was a premature birth at 34 weeks, but the baby died 12 days later. During the year of her last pregnancy, she was diagnosed with systemic lupus erythematous. She had a transiently positive (falsely positive) rapid plasma reagin and transiently elevated activated partial thromboplastin time. Her recent brain MRI scan revealed multiple chronic ischemic infarct-like changes. Her thrombophilic workup revealed positive anticardiolipin, IgG, and IgM, greater than the 99th percentile for that laboratory.

Biological basis

Etiology and pathogenesis

Antiphospholipid syndrome can be divided into primary and secondary. Primary antiphospholipid syndrome is an idiopathic disease associated with clinical manifestations and laboratory findings consistent with antiphospholipid syndrome, but in the absence of an underlying disease process. Secondary antiphospholipid syndrome is associated with systemic disorders, the commonest being systemic lupus erythematous. Other underlying causes include infections (mycoplasma, malaria, Lyme, etc.) or drugs (interferons, sulfonamides, etc.).

The hemostasis involves balance between procoagulant and anticoagulant mechanisms. The latter tend to predominate to ensure good laminar flow in the vessels.

Intravascular thrombosis is usually triggered by endothelial injury, which releases the tissue factor, the activator of the intrinsic coagulation pathway. The ensuing prothrombotic cascade involving platelets and clotting factors leads to formation of the blood clot. Thrombosis in antiphospholipid syndrome is believed to involve all these events, which mimic endothelial injury predisposing to thrombosis.

Endothelial activation. The mechanism by which antiphospholipids activate the endothelium is not clear. Mannose-binding lectin binds to β2GPI in the endothelium, triggering complement activation and thrombin generation. β2GPI binds to annexin A2, an activating endothelial receptor (100). Annexin may also be induced by oxidative stress (62). Several other receptors have been identified besides annexin A2 (98). Endothelial priming with TNF-alpha amplifies thrombin generation (34).

Neutrophil extracellular traps. Neutrophil extracellular traps are webs of extracellular chromatin and antimicrobial proteins resulting from neutrophil death (15). Neutrophil extracellular trap release is facilitated by immune complexes, interleukins (IL-8), tumor necrosis factor, granulocyte colony stimulating factors, activated endothelial cells, platelets, and reactive oxygen species. Neutrophil extracellular traps serve as a scaffold onto which aggregates of platelets and erythrocytes adhere. At the same time, neutrophil extracellular traps bind to fibrinogen, fibronectin, and von Willebrand factor and stabilize the clot (82).

Prothrombotic upregulation. Activation of prothrombotic factors in antiphospholipid syndrome is presumed to involve three distinct entities, although these mechanisms have not been elucidated in their entirety at present.

Platelet activation. Antiphospholipids amplify platelet activation by endothelium. The anti-β2GPI antibody binds to the GPIb subunit of the GPIb/IX/V receptor on the platelet surface, leading to thromboxane production and activation of the phosphoinositide-3 kinase/Akt pathway (92). The increased thromboxane production, in turn, contributes to platelet aggregation and activation.

Complement. Increased complement production in patients with stroke contributes to thrombosis (30). This appears to be related to complement factors C5 and C6 and is strongly associated with IgG-type antiphospholipids (42).

Dysregulation of fibrinolysis. Fibrin cross-linkage, which leads to clot organization, is countered by tissue plasminogen activator (tPA). The latter is activated to plasmin and aids in fibrinolysis and clot disruption. Antiphospholipid syndrome is often associated with other antibodies like anti-annexin 2, anti-tPA, and antiplasmin (29; 99; 24). Annexin 2 is involved in colocalizing endothelial tPA and plasminogen in a physiological state, resulting in plasmin production. These antibodies inhibit clot dissolution (61).

Anticoagulant downregulation.

Activated protein C inhibition. The major anticoagulant pathway in the body involves protein C and protein S. Endothelial activation activates protein C, which together with protein S, inactivates factors Va and VIIIa. β2GPI-anti-β2GPI complex binds to activated protein C (APC) complex, thus, inhibiting its anticoagulation activity (88).

Other mechanisms. Most other mechanisms are under investigation, including annexin 5, a protein that appears to contribute to an anticoagulant coating on endothelial cells and platelets. It appears that the β2GPI-anti-β2GPI complex may inhibit annexin 5, triggering placental thrombosis and fetal loss (79; 80). Inhibition of activated factor X and tissue factor pathway also play a role (89; 43).

A now widely accepted concept in the pathogenesis of antiphospholipid syndrome is the “2-hit hypothesis” (93; 47). The presence of antiphospholipids induces thrombophilia, but their presence alone is not sufficient for thrombosis to occur. Thus, the presence of antiphospholipids can be described as a first hit. A second hit, like infection or systemic inflammation, is often required for the thrombotic response to occur (83; 93; 57). In vitro, a lipopolysaccharide as an external antigen was required to set up thrombosis in rats with anti-β2GPI IgG (42). However, this hypothesis only applies to the vascular manifestation and does not entirely describe the obstetric manifestations of the disease (64).

The mechanisms resulting in obstetric complications are similar to the ones involved in vascular thrombosis. The chief processes described in this clinical setting include the following (18):

• Thrombosis of spiral arterioles.

• Interference of thromboxane/prostacyclin balance.

• Interference with trophoblastic activity.

The hypercoagulable state of antiphospholipid syndrome leads to thrombosis of spiral arterioles, thus, contributing to placental insufficiency. This vasculopathic state is further worsened by increased thromboxane presentation, which promotes platelet aggregation and vasoconstriction, thus, contributing to placental infarction. Other mechanisms like protein C and protein S activity and reduction of annexin 5 are other mechanisms contributing to the hypercoagulable, vasculopathic state.

Alteration of trophoblastic function, mediated by direct antiphospholipid antibody targeting of trophoblastic β2GPI, is a nonthrombotic aspect of the pathogenesis in this setting. It results in alteration of trophoblast differentiation and maturation, direct cellular damage, and apoptosis, thus, contributing to a high incidence of fetal loss. This has been confirmed to high incidence by animal studies in which murine models inoculated with antiphospholipids caused early resorption of pregnancy (76; 44).

Epidemiology

The presence of antiphospholipid antibodies in an individual does not always predict the development of clinical syndrome. Various studies have shown that 1% to 5% of the general population test positive for antiphospholipid antibodies (75; 12; 13).

Asymptomatic patients with positive antiphospholipids have a 0% to 4% risk of thrombosis (46). Most antibodies are anticardiolipin, followed by lupus anticoagulant and anti-β2GPI (11). These antibodies result from exposure to infections, malignancies, or drugs. They are usually present at low levels and transiently (91). Because of low levels and transient presence, diagnosis of antiphospholipid syndrome requires persistent, moderate to high levels of these antibodies (65).

The risk of thrombosis is higher if antiphospholipids are associated with a primary disease (58). Common underlying primary disorders include systemic lupus erythematous, rheumatoid arthritis, malignancies, and infections like syphilis, hepatitis C, HIV, cytomegalovirus, tuberculosis, or leprosy (81; 17; 97). For example, for over 20 years, the risk of developing antiphospholipid syndrome has been between 30% and 70% in patients with systemic lupus erythematous (70).

There are few longitudinal and demographic studies of antiphospholipid syndrome. The prevalence of antiphospholipids was as low as 2% in Afro-Caribbean countries and as high as 51% in some Asian countries (13). Caucasians seem to have a higher risk of thrombosis compared to Chinese patients (66). Data for other populations are lacking. The antiphospholipids have also been associated with certain haplotypes like HLA-DR4, HLA-DR7, HLA-DRw53, and HLA-DQB1-0302 (90). These haplotypes are, in turn, often found in patients with autoimmune diseases, especially systemic lupus erythematous.

The commonest presentation of antiphospholipid syndrome is venous thrombosis, usually as deep venous thrombosis (19). The frequency of antiphospholipids in patients with deep venous thrombosis ranges from 5% to 30%.

Arterial thrombosis accounts for 30% of all thromboses associated with antiphospholipid syndrome (40). The most common are transient ischemic attack and stroke followed by coronary and peripheral arterial occlusion (49). Although an interaction of antiphospholipids with patent foramen ovale was suspected, no association between the antiphospholipid, patent foramen ovale, and stroke incidence was found (77).

The most common obstetric complication is fetal loss.

Up to 25% of recurrent miscarriages can be attributed to antiphospholipid syndrome (32; 44). Intrauterine growth retardation was found in 13.7% of women with antiphospholipid syndrome (96). The rate of early fetal loss in women with antiphospholipid syndrome ranges between 17.1% and 35.4%. Late fetal loss occurs in 16.9%, and preterm labor in approximately 35%, of pregnant women with antiphospholipid syndrome (21; 20).

Prevention

Prevention of antiphospholipid syndrome-related thrombosis has usually revolved around the presence of index events, or high-risk antibody profile, or both (high titers of anticardiolipin, anti-β2GPI, lupus anticoagulant).

Asymptomatic carriers. The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study, a randomized controlled trial, showed that in asymptomatic carriers of persistently positive antiphospholipid antibody, the rate of new thrombosis was low and that low-dose (81 mg) aspirin failed to prevent thrombosis (36). Also, most thrombotic events in both study arms were associated with other prothrombotic factors.

An analysis of 5 international cohort studies found a protective effect of low-dose aspirin against a first arterial, but not venous, thrombosis in patients with antiphospholipid antibodies, systemic lupus erythematosus, and asymptomatic antiphospholipid carriers (02).

The ALIWAPAS study, a prospective, multicenter, randomized, open, controlled trial found that adding low-intensity warfarin to low-dose aspirin did not provide additional protection against a first thrombosis in patients with antiphospholipid antibodies and systemic lupus erythematosus or obstetric morbidity, or both (28). The combination treatment caused more episodes of bleeding.

In asymptomatic carriers with either a low- or high-risk antiphospholipid profile, low-dose aspirin (75 to 100 mg daily) is recommended. In patients with systemic lupus erythematosus, without thrombotic or obstetric complications, low-dose aspirin may be considered in low-risk antiphospholipid profile and is recommended in high-risk antiphospholipid profile. Nonpregnant women with a history of obstetric antiphospholipid syndrome only (with or without systemic lupus erythematosus) may be offered low-dose aspirin after adequate risk-benefit evaluation (95).

Antiphospholipid syndrome presenting as venous thrombosis. Patients with venous thrombosis and 1 positive reading of antiphospholipid or definite antiphospholipid syndrome had a low recurrence rate at an international normalized ratio of 2 to 3 (87). Warfarin is preferred to rivaroxaban, unless contraindicated due to subtherapeutic international normalized ratio despite compliance, allergy, or intolerance. Rivaroxaban should be avoided in patients with triple positivity. In patients with unprovoked venous thrombosis, prophylaxis duration is long term. Duration or prophylaxis for provoked thrombosis is the same as in patients without antiphospholipid syndrome, but longer duration should be considered in those with high-risk antiphospholipid profiles.

In patients with definite antiphospholipid syndrome and recurrent venous events despite an international normalized ratio of 2 to 3, the addition of low-dose aspirin, an increase of target international normalized ratio to 3 to 4, or a change to low molecular weight heparin may be considered (95).

Antiphospholipid syndrome presenting as arterial ischemia. The Antiphospholipid Antibodies and Stroke Study (APASS) was a prospective cohort study within the Warfarin vs. Aspirin Recurrent Stroke Study (WARSS), a randomized, double-blind trial comparing 325 mg of aspirin with warfarin in patients with a previous ischemic stroke and antiphospholipids. Warfarin was not superior to aspirin. The limitations of the study were diagnosis of the antiphospholipid syndrome based on a single test and lack of patients with high-titer positivity (60).

A systematic review of 16 studies found that patients with stroke and 1 reading of antiphospholipid test had no increased risk compared to those without antiphospholipids (87).

The American Stroke Association guidelines recommend antiplatelet monotherapy for patients with cryptogenic ischemic stroke or transient ischemic attacks and positive antiphospholipid antibodies who do not meet the criteria for antiphospholipid syndrome and for patients who meet the criteria for antiphospholipid syndrome but in whom anticoagulation has not yet begun (54). For those who meet the antiphospholipid syndrome criteria, anticoagulation with a target international normalized ratio of 2 to 3 is recommended (55; 87; 54; 95).

Antiphospholipid syndrome presenting with recurrent events. If thromboembolism recurs despite reaching the target international normalized ratio of 2 to 3, retrospective data suggest a lower risk of recurrence at a target international normalized ratio greater than 3.0 and a higher mortality due to recurrent thrombosis rather than bleeding (85; 55; 87; 23).

However, in a randomized, double-blind clinical trial of 114 patients, high-intensity (target international normalized ratio: 3.0 to 4.0) was not more effective than moderate-intensity anticoagulation (27). Additionally, the Warfarin in the Anti-Phospholipid Syndrome (WAPS) trial failed to demonstrate superiority of high-intensity warfarin treatment compared to medium-intensity anticoagulation (41). Nevertheless, increasing the target international normalized ratio to 3 to 4, adding low-dose aspirin, or switching to lower molecular weight heparin was suggested (95). The risk of hemorrhagic complications may be higher with the combination therapy (72).

Antiphospholipid syndrome presenting with obstetric complications. The recommendations vary with the type of presentation and are tailored to the clinical situation in close collaboration with the OBGYN specialist.

Hydroxychloroquine is often added to the regimen of patients with secondary antiphospholipid syndrome associated with systemic lupus erythematosus (75; 86; 87). However, hydroxychloroquine had no independent protective effect in a meta-analysis of 497 subjects (02).

Thrombotic events in asymptomatic antiphospholipid patients have often been correlated with the presence of other thrombotic risk factors. This is especially important given the “2-hit” pathogenetic theory of thrombosis development (64). Thus, it is important to exercise; avoid smoking and oral contraceptives; and treat hypertension, hyperlipidemia, and diabetes. Lastly, high-risk situations like surgery or prolonged immobilization may benefit from low molecular weight heparin.

Differential diagnosis

The clinical presentation of antiphospholipid syndrome is usually unique to the system of involvement. Therefore, a system-based approach is best in describing the possible differential diagnosis of antiphospholipid syndrome.

Hematological/vascular presentation. Antiphospholipid syndrome presents with thrombosis in both arterial as well as venous beds. However, because the first episodes are usually isolated, antiphospholipid syndrome should be considered in cases with unusual presentations.

Venous thrombosis. Patients presenting with deep venous thrombosis and pulmonary embolisms may often have other risk factors for venous thrombosis like vascular stasis and endothelial injury. Thus, a differential in such cases includes other diagnoses:

• Cancers (eg, ovarian cancer or small cell lung cancer) • Myeloproliferative disorders • Oral contraceptive pills • Inherited and acquired coagulation factor disorders (eg, protein C and protein S deficiency, Factor V Leiden) • Nephrotic syndrome

Arterial ischemia. Traditional vascular risk factors like hypertension, diabetes, atherosclerosis, and cardioembolic causes are usually the top differential for any arterial infarction. However, demographically unusual presentations, like children or adults 45 years old and younger, should prompt investigations for other causes like antiphospholipid syndrome. Other causes for this clinical presentation must be part of the work up and include:

• Vasculitis, including diseases such as polyarteritis nodosa • Thrombotic thrombocytopenic purpura (TTP)

Arterial and venous thromboses. The following are a few conditions that can lead to both arterial and venous thrombosis:

• Homocysteinemia • Inherited and acquired disorders of coagulation (Protein C and protein S deficiency, dysfibrinogenemia) • Heparin-induced thrombocytopenia • Disseminated intravascular coagulation

Some prothrombotic or anticoagulant hematological conditions, such as clotting factor deficiency (Factors VIII, IX, XI, and XII), disseminated intravascular coagulation, dysfibrinogenemia, and hyperfibrinogenemia, also lead to an elevated aPTT-like antiphospholipid syndrome. However, in these conditions addition of normal plasma often corrects the aPTT, a feature not seen with antiphospholipid syndrome.

Obstetric complications. Recurrent fetal loss can be secondary to other abnormalities such as paternal or maternal chromosomal disorders, or maternal reproductive system anatomic abnormalities. However, in these conditions, fetal loss is usually in the early (less than 6 weeks) or mid- (6 to 9 weeks) fetal period. Antiphospholipid syndrome typically causes fetal loss after 9 weeks. Also, when other risk factors of preeclampsia (maternal diabetes, early or late maternal age, history of gestational hypertension) have been ruled out, antiphospholipid syndrome should be considered in the differential.

Diagnostic workup

The diagnostic criteria for antiphospholipid syndrome were revised in 2006 (65; 38). Based on this revision, at least one of the clinical and one of the laboratory criteria should be met for the diagnosis of antiphospholipid syndrome.

Clinical criteria.

Vascular thrombosis. Evidence of arterial or venous or small vessel thrombosis in vascular beds of any tissue or organ. Diagnostic/confirmatory imaging or histopathology should confirm this. The histopathology should reveal evidence of thrombosis in the absence of significant inflammation of the vessel wall.

Obstetric. Pregnancy-related morbidity has always been the cornerstone of diagnosis of antiphospholipid syndrome in women of childbearing age (08; 44).

These chiefly include the following:

	• Recurrent fetal loss (≥3) before 10 weeks of pregnancy after excluding chromosomal or anatomic causes.
	• Any fetal loss at or after 10 weeks of pregnancy with normal fetal morphology.
	• Premature birth secondary to preeclampsia/eclampsia of a morphologically normal neonate.
	• Premature birth secondary to uteroplacental insufficiency.

Laboratory criteria. This diagnostic criterion requires two or more abnormal laboratory measurements at least 12 weeks apart of the following antibodies:

	• Lupus anticoagulant, detected according to the guidelines of the International Society on Thrombosis and Hemostasis.
	• Anticardiolipin, IgG, or IgM type present in moderate to high titer (> 40 GPL or MPL or > 99th percentile) by a standardized ELISA.
	• Anti-β2GPI, IgG, or IgM type present in moderate to high titer (> 99th percentile) by a standardized ELISA.

Risk stratification is based on the antiphospholipid profile. High-risk antiphospholipid profile is characterized by detection of lupus anticoagulant on 2 or more occasions at least 12 weeks apart, or of double (any combination of lupus anticoagulant, anticardiolipin antibodies, or anti-β2GPI) or triple (all 3 subtypes) antiphospholipid positivity, or the presence of persistently high antiphospholipid titers.

A low-risk antiphospholipid profile is seen in isolated anticardiolipin or anti-β2GPI antibodies at low-medium titers, particularly if transiently positive (87).

Management

The management of antiphospholipid syndrome revolves around the prevention of thrombotic complications as well as the treatment of acute episodes.

Acute treatment. Most thrombotic events with antiphospholipid syndrome should be treated as patients with acute thrombosis. Therefore, those with arterial/venous thrombosis should be treated with IV thrombolytics/fibrinolytics depending on the circulation involved as well as the standard recommendation for that organ system.

Association of antiphospholipid syndrome with systemic vasculitis is rare. The pathogenesis is usually vascular thrombotic episodes with or without associated vasculopathy. Some manifestations such as livedo reticularis and retinal vasculitis are attributed to vasculitis. Differentiation between vasculitis and antiphospholipid antibodies mediated thrombosis is critical to determine appropriate antithrombotic therapy versus immunosuppressive therapy (56).

Treatment of CAPS. CAPS has a mortality of 50% and requires ICU care. The combination of anticoagulation, corticosteroids, and plasma exchange or IVIG is recommended over other forms of treatment (16). Cyclophosphamide improves outcome only in patients who also have systemic lupus erythematosus (09). Rituximab and eculizumab may have a role in CAPS management (37; 10).

Novel oral anticoagulants for thrombotic prophylaxis in antiphospholipid syndrome. The novel oral anticoagulants have several advantages over warfarin. These agents, including direct thrombin inhibitor (dabigatran) and anti- Factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) have more predictable anticoagulant effects than warfarin, do not require monitoring, and do not interact with foods, alcohol, and drugs and have already been FDA-approved for several clinical indications. However, inadequate evidence exists on their use in patients with antiphospholipid syndrome (01).

The randomized controlled trial, Rivaroxaban Versus Warfarin to Treat Patients with Thrombotic Antiphospholipid Syndrome with or without Systemic Lupus Erythematosus (RAPS), failed to reach noninferiority due to a 2-fold increase in thrombin potential in patients receiving rivaroxaban. However, the authors concluded that rivaroxaban might be an effective and safe alternative to warfarin as there was no increased thrombotic risk in the rivaroxaban arm compared to warfarin (26). Criticisms of this trial include exclusion of high-risk patients and relatively short period of follow-up.

The Trial on Rivaroxaban in Anti-Phospholipid Syndrome (TRAPS), which compares rivaroxaban with standard-intensity warfarin, was prematurely stopped because all thrombotic events occurred in the rivaroxaban arm in triple-positive patients (74).

A systematic review of the literature identified 122 patients with antiphospholipid syndrome treated with direct oral anticoagulants; 19 experienced recurrent thrombosis and three patients who had no recurrence while treated with warfarin developed recurrent thrombosis after switching to direct oral anticoagulants. Positivity for all three laboratory criteria for antiphospholipid syndrome was associated with a 3.5-fold increased risk for recurrent thrombosis (33).

At present there is a need for more randomized controlled trials using strong clinical endpoints before any definite conclusions can be drawn regarding the safety and efficacy of these novel oral anticoagulants in patients with the antiphospholipid syndrome. This may be difficult to achieve as an attempted study in Canada comparing rivaroxaban and warfarin was stopped due to failure to enroll sufficient patients (59).

Special considerations

Pregnancy

Treatment of obstetric antiphospholipid syndrome depends on the type of clinical presentation prior to the diagnosis of antiphospholipid syndrome in these patients. Aspirin, low molecular weight heparin, or both are the cornerstones of therapy for obstetric antiphospholipid syndrome. Multidisciplinary collaboration with the OBGYN specialist is crucial for the management of these patients.

Anesthesia

Perioperative risks in patients with antiphospholipid antibodies include both thrombosis and bleeding. Thrombosis can occur spontaneously or can be potentially precipitated by surgical intervention, infections, and recent change in anticoagulation therapy. It is recommended to perform clotting factor assays in addition to routine studies before surgery as antiphospholipid antibody syndrome is frequently associated with clotting factor deficiencies and thrombocytopenia. There is no consensus to ensure the optimal level of anticoagulation perioperatively (31). Certain general measures are taken to minimize the risk, including antithrombotic stockings, warm fluids to prevent hypothermia, adequate hydration, and prophylactic antibiotics to help prevent infection. Subcutaneous heparin is used in most patients in the hospital to prevent deep venous thrombosis (78).