Clinical manifestations

Presentation and course

	• Antiphospholipid syndrome presents as thrombosis associated with persistent titers of aPL.
	• The most involved systems are the hematologic, nervous, cardiac, dermatologic, pulmonary renal, and gynecologic.
	• Catastrophic antiphospholipid syndrome is characterized by simultaneous thrombosis of at least three organs or systems.

Most antiphospholipid syndrome manifestations are attributed to vascular thrombosis.

Nervous system. Arterial thrombosis occurs most commonly in cerebral circulation (60). Stroke and transient ischemic attack were among the most common manifestations in the “Euro-Phospholipid” cohort (24). However, in the Physicians' Health Study, which enrolled 22,071 male patients, high titers and anticardiolipin IgG above the 95th percentile were associated with pulmonary embolism and venous thromboembolism but not ischemic stroke (59).

Cerebral venous sinus thrombosis is another complication of antiphospholipid syndrome (32). Embolism from large extracranial vessels, valvular vegetations, endocarditis, and intracardiac thrombi may also occur. Screening for antiphospholipid antibodies is recommended in young adults (< 50 years) with ischemic stroke (67).

Other neurologic conditions associated with antiphospholipids include autoimmune chorea, migraine headaches, encephalopathy, seizures, dementia, Guillain-Barre syndrome, psychosis, and transverse myelopathy (26; 90; 88; 62).

Heart. Mural thrombosis, micro thrombi, and coronary artery disease often occur in antiphospholipid antibody syndrome. Noninfectious endocarditis, valvular vegetations, stenosis, and 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 (113).

Skin. Livedo reticularis and livedo vasculitis should raise the suspicion of antiphospholipid syndrome. Others include thrombophlebitis, ulcerations, digital gangrenes, and splinter-hemorrhages. The latter are, however, not considered diagnostic.

Kidney. 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 directly related to antiphospholipid syndrome if they result from the thrombotic events described above.

Lungs. The most common respiratory manifestations include pulmonary embolism and pulmonary arterial thrombosis. Nonthrombotic vasculopathy and pulmonary hypertension have been reported as well.

Gastrointestinal system. The gastrointestinal manifestations include Budd-Chiari syndrome, portal and mesenteric vein thrombosis, ischemic colitis, and splenic/hepatic/intestinal infarctions. Other complications include esophageal and colon perforation and cholecystitis.

Blood. The commonest manifestation, thrombocytopenia due to splenic sequestration, rarely leads to bleeding. Similar mechanisms lead to hemolytic anemia and hypoprothrombinemia, which are suspected if there is prolonged bleeding time and are confirmed by deceased prothrombin levels.

Other arteriovenous manifestations. Other 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. The obstetric complications are recurrent miscarriage before the tenth week of gestation, loss of a morphologically normal fetus after 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. 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. The criteria for the diagnosis of catastrophic antiphospholipid syndrome are as follows (09; 27):

• Involvement of three or more 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 catastrophic antiphospholipid syndrome includes respiratory failure, stroke, renal impairment, and cutaneous manifestations and follows a fulminant course. The most involved systems include renal, pulmonary, neurologic, cardiac, and cutaneous (07). Thrombosis of the microvasculature of these systems is the unifying pathological feature (10). The precipitating events are infections, surgery, or drugs. Disseminated intravascular coagulation, an unusual manifestation of isolated antiphospholipid syndrome, has been frequently associated with catastrophic antiphospholipid syndrome, probably secondary to widespread thrombotic activation.

Other presentations. Although not widely accepted, antiphospholipid syndrome may manifest in two other forms: pre-antiphospholipid syndrome and microangiopathic antiphospholipid syndrome.

Pre-antiphospholipid syndrome is a condition that may presage the development of antiphospholipid syndrome: livedo reticularis, chorea, thrombocytopenia, fetal loss, or valve lesions (08).

Microangiopathic antiphospholipid syndrome describes microvascular occlusions associated with antiphospholipid antibodies that share common triggers like infection or drugs, and that have similar clinical as well as hematological features such as thrombocytopenia, hemolytic anemia, thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and HELLP syndrome (08).

Prognosis and complications

The prognosis of antiphospholipid syndrome depends on the type of vessel and distribution of vascular territory involved. The risk of recurrent thrombotic event is 91% of cases in the initial vascular type (102). The risk of recurrence depends on anticoagulation and target international normalized ratio (INR) 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 catastrophic antiphospholipid syndrome as it can approach 50% mortality (09; 45).

High titers of IgM anticardiolipin antibodies correlate National Institutes of Health stroke scale acutely, and higher IgG anticardiolipin antibody titers with disability at three months (101).

Complications of antiphospholipid syndrome are associated with the primary presentation. Arterial strokes increase the 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. Deep venous thrombosis may result in pulmonary embolism and hepatic vein thrombosis 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 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 revealed multiple chronic ischemic infarct-like changes. Thrombophilia workup revealed positive anticardiolipin, IgG, and IgM, greater than the 99th percentile for that laboratory.

Biological basis

	• Antiphospholipid syndrome is idiopathic or the result of an underlying process.
	• The mechanism of antiphospholipid syndrome is alteration of the balance between coagulation and anticoagulation.
	• Multiple elements of the coagulation process are either upregulated or downregulated, leading to excessive coagulation.

Etiology and pathogenesis

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

Hemostasis ensures that the balance between coagulation and anticoagulation is tipped towards the latter to ensure optimal blood flow. This balance is altered by the antiphospholipid syndrome leading to excessive coagulation, which has various clinical consequences depending on the organ or tissue affected.

Prothrombotic upregulation. Intravascular thrombosis, usually triggered by endothelial injury, releases the tissue factor, thus triggering the intrinsic coagulation pathway and formation of the blood clot. Thrombosis in antiphospholipid syndrome is believed to mimic endothelial injury predisposing to thrombosis.

Endothelial activation. Mannose-binding lectin binds to endothelial β2GPI triggering complement activation and thrombin generation. Surface receptors for β2GPI and anti- β2GPI include apolipoprotein E receptor 2 (apoER2) and the complex annexin A2 and TLR4. Activation of p38 MAPK results in upregulation of tissue factor (118). Endothelial activation is modulated by Kruppel-like factors resulting in decreased nitric oxide synthesis (04). Migration of NF-KB from cytoplasm into the nucleus enhances the expression of tissue factor and cell adhesion molecules (43).

Annexin A2 is a tPA endothelial receptor (127). Endothelial priming with TNF-alpha amplifies thrombin generation (44). During pregnancy, β2GPI binds to the uterine endothelial cells and trophoblast. Fetal loss was associated with C3 and C9 deposition (02).

Tissue factor activity upregulation. Antiphospholipid antibodies enhance the production of tissue factor by endothelial cells (93). Additionally, inhibition of tissue factor pathway inhibitor type 1 (TFPI) by IgG from patients with lupus stimulates thrombin generation (01; 75).

Platelet activation. Binding by β2GPI on the surface of unstimulated platelet is limited. Once exposed to stress or thrombin, platelets become activated (119). 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 (109). Thromboxane contributes to platelet aggregation and activation. Additionally, exposure of platelets to aPL antibodies increases expression of GP IIb/IIIa and GPIIIa on platelet surface (47). Healthy platelets in contact with calcium and prothrombin and presence of anti-GPI become activated. This may explain why vitamin K antagonists are more effective anticoagulants than factor Xa (31).

Complement activation. Complement activation contributes to thrombosis (37). This appears to be related to C5 and C6 and is strongly associated with IgG-type antiphospholipids (53).

Neutrophil activation. The presence of aPL antibodies, while necessary, does not trigger the clinical manifestations of antiphospholipid antibody syndrome. In presence of lipopolysaccharides, the activation of neutrophils by aPL antibodies was significantly increased through the toll-like receptor, TLR-4 (61). Additionally, the release of neutrophil extracellular traps (NETosis) by antibodies anti-β2GPI also triggers thrombosis (79). Neutrophil extracellular traps are webs of extracellular chromatin and antimicrobial proteins resulting from neutrophil death (19). Their release is facilitated by immune complexes, interleukins (IL-8), tumor necrosis factor, granulocyte colony stimulating factors, activated endothelial cells, platelets, and reactive oxygen species. The resulting scaffold traps platelets, erythrocytes, fibrinogen, fibronectin, and von Willebrand factor and stabilizes the clot (99). At the same time, neutrophil extracellular trap promotes thrombin generation (123).

Monocyte activation. The monocytes in patients with antiphospholipid syndrome increase expression of tissue factor on their surface and contribute to thrombosis (77).

Inhibition of fibrinolysis. Thrombosis is disrupted by tissue plasminogen activator (tPA). The annexin 2 (A2) complex, a cell surface receptor for tPA, facilitates generation of plasmin and clot dissolution (63; 76). Antiphospholipid syndrome is often associated with other antibodies against annexin 2, tPA, and plasmin (36; 124; 29). These β2GPI is a cofactor for tPA-mediated cleavage of plasminogen. Therefore, anti-β2GPI antibodies prevent plasmin formation (20). Moreover, plasminogen activator inhibitor-1 is upregulated (112).

Anticoagulant downregulation.

Activated protein C inhibition. The major anticoagulant pathway involves protein C and protein S. Activation of endothelium in turn activates protein C, which together with protein S, inactivates the coagulation factors Va and VIIIa. β2GPI-anti-β2GPI complex binds to activated protein C (APC) complex, thus, inhibiting its anticoagulation activity (106).

Prevention of antithrombin activation. Full activation of antithrombin is prevented by the aPL antibodies with affinity for heparan sulphate, an endothelial anticoagulation modulator. These antibodies inhibit the heparin-accelerated binding of antithrombin III to thrombin (110). In addition, antibodies against factors II, IX, and Xa prevent their inhibition by thrombin (66; 126; 125).

Other mechanisms. Annexin 5 is a protein that contributes to the anticoagulant coating on endothelial cells and platelets. The β2GPI-anti-β2GPI complex may inhibit annexin 5, triggering placental thrombosis and fetal loss (96; 97). Inhibition of activated factor X and tissue factor pathway also plays a role in coagulopathy (107; 54).

The “2-hit hypothesis” suggests that mere presence of antiphospholipid antibodies, while necessary, is not sufficient to cause thrombosis (111; 58). Thus, antibody presence can be described as a first hit. A second hit, like infection or systemic inflammation, is often required for the thrombotic response to occur (100; 111; 71). In vitro, a lipopolysaccharide was required to trigger thrombosis in rats with anti-β2GPI IgG (53). This hypothesis only applies to the vascular complications and does not entirely describe the obstetric manifestations of the disease (80).

Obstetric complications are thought to result from vascular thrombosis (23).

However, thrombosis of uterine spiral arterioles is rare. More often found are decidual inflammation, deposition of complement C4d, impaired spiral artery remodeling by extra-villous trophoblasts, and decreased vasculo-syncytial membranes (120). Complement activation in the placenta mediates the inflammatory response. Alteration of trophoblast differentiation and maturation, direct cellular damage, and apoptosis contributes to fetal loss. Mice inoculated with antiphospholipids experienced early resorption of pregnancy (92; 55). Increased thromboxane production further promotes platelet aggregation, vasoconstriction, and placental infarction. Additionally, protein C and protein S activity and reduction of annexin 5 contribute to the hypercoagulable and vasculopathic state.

The catastrophic antiphospholipid syndrome seems to be related to endothelial and platelet activation (17). Approximately 60% of patients have rare germline variants of complement regulatory gene compared to 23.3% of normal controls (30).

The occlusive vasculopathy in chronic form is characterized by progressive expansion of intima due to endothelial cell proliferation (03). Additional factors are vascular smooth proliferation and deposition of proteoglycan rich extracellular matrix (03).

Epidemiology

	• The antiphospholipid antibodies are detected in a small proportion of asymptomatic individuals.
	• These antibodies have multiple etiologies and usually decrease over time.
	• aPTT is an unreliable test for detecting antiphospholipid antibodies.
	• Specific tests for each type of antibody are required for diagnosis of unexplained thrombosis.
	• The risk of thrombosis is higher if the antibodies are associated with a primary disease.

The prevalence of antiphospholipid antibody syndrome is 40 to 50 per 100,000 and the annual incidence is 1 to 2 per 100,000 (40). The aPL antibodies alone do not always trigger the clinical syndrome. Between 1% to 10% of the asymptomatic population test positive for antiphospholipid antibodies, and the titers usually decline with time (121; 16). aPTT is prolonged only in 40% to 50% of patients with lupus anticoagulant and not in those with anticardiolipin antibodies. Definitive tests like ELISA for anticardiolipin antibodies, dRVVT for lupus anticoagulant, hexagonal phospholipid neutralization procedure, and beta-2-GP-I (IgG, IgA, and IgM) are more useful in patients with unexplained thromboembolism (15).

Asymptomatic patients with positive antibodies have a 0% to 4% risk of thrombosis (57). Most antibodies are anticardiolipin, followed by lupus anticoagulant and anti-β2GPI (14). They result from exposure to infections, malignancies, or drugs, and are usually present transiently at low levels (108). Diagnosis of antiphospholipid syndrome requires persistent, moderate to high levels of these antibodies (81).

The risk of thrombosis is higher when the antibodies are associated with a primary disease (72). Common underlying primary disorders include systemic lupus erythematous, rheumatoid arthritis, malignancies, and infections like syphilis, hepatitis C, HIV, cytomegalovirus, tuberculosis, or leprosy (98; 22; 117). For example, over 20 years, the risk of developing antiphospholipid syndrome is between 30% to 70% in patients with systemic lupus erythematous (86).

The prevalence of antiphospholipid antibodies was as low as 2% in Afro-Caribbean countries and as high as 51% in some Asian countries (16). Caucasians seem to have a higher risk of thrombosis compared to Chinese patients (82).

Venous thrombosis is the most common presentation of antiphospholipid syndrome, usually as deep venous thrombosis (24). The frequency of antiphospholipid antibodies in patients with deep venous thrombosis ranges from 5% to 30%.

Arterial thrombosis, in the form of TIA, stroke, coronary syndrome, or peripheral arterial occlusion, accounts for 30% of all thromboses associated with antiphospholipid syndrome (51; 60). Although an interaction of antiphospholipids with patent foramen ovale was suspected, no association between the antiphospholipid, patent foramen ovale, and stroke incidence was found (94).

Fetal loss is the most common obstetric complication of antiphospholipid syndrome, which is responsible to 25% of recurrent miscarriages (39; 55). 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 (26; 25).

Intrauterine growth retardation was found in 13.7% of women with antiphospholipid syndrome (116)

Prevention

	• A moderate to high titer antibody warrants avoidance of estrogen supplements and active perioperative thromboprophylaxis.
	• Low-dose aspirin prevents first arterial ischemic event in asymptomatic antibody carriers, with or without systemic lupus erythematosus or obstetric complications.
	• Unfractionated heparin or low molecular weight heparin followed by oral warfarin with target international normalized ratio (INR) 2 to 3 is preferred for prevention of recurrent venous thrombosis.
	• High-intensity anticoagulation INR 3 to 4 is not superior to moderate intensity anticoagulation.
	• Recurrent venous thrombosis despite INR 2 to 3 may benefit from additional low-dose aspirin, increasing INR to 3 to 4 or low molecular weight heparin.
	• Antiplatelet monotherapy is recommended for patients with cryptogenic stroke/TIA, with one reading of positive antiphospholipid antibodies.
	• Arterial thrombosis and antiphospholipid syndrome may benefit from anticoagulation with warfarin to INR 2 to 3.

Asymptomatic carriers. Thrombotic events in otherwise 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 (80). Exercising, avoiding smoking and oral contraceptives, and treating the cerebrovascular risk factors like hypertension, hyperlipidemia, and diabetes are all useful. Additionally, high-risk situations like surgery or prolonged immobilization may benefit from low molecular weight heparin.

The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study, a randomized controlled trial in asymptomatic carriers of persistently positive antiphospholipid antibody, demonstrated a low risk of thrombosis. Low-dose (81 mg) aspirin failed to prevent thrombosis (46).

However, analysis of five international cohort studies found a protective effect of low-dose aspirin against a first arterial, but not venous, thrombosis in patients with antiphospholipid antibodies with systemic lupus erythematosus, and asymptomatic carriers (06).

ALIWAPAS study was a prospective, multicenter, randomized, open, controlled trial in patients with antiphospholipid antibodies and systemic lupus erythematosus or obstetric morbidity, or both (35). Low-intensity warfarin addition to low-dose aspirin did not provide additional protection against a first thrombosis. Moreover, the combination caused more episodes of bleeding.

In asymptomatic carriers, low-dose aspirin (75 to 100 mg daily) should be individualized based on risk. 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 may be offered low-dose aspirin (114).

Antiphospholipid syndrome presenting as venous thrombosis. Venous thrombosis has a low recurrence rate at an international normalized ratio (INR) of 2 to 3 (105). Warfarin is the preferred anticoagulant, unless there is difficulty obtaining consistent INR, allergy, or intolerance to it. Rivaroxaban may be used instead, but it should be avoided in patients with triple antibody positivity.

Unprovoked venous thrombosis warrants long-term prophylaxis. However, the benefit of long-term anticoagulation in patients with thrombosis provoked by surgery, for example, or with declining antibody titers over time, is less clear. Longer duration should be considered if there is a high-risk antiphospholipid profile.

In definite antiphospholipid syndrome and recurrent venous events despite INR of 2 to 3, addition of low-dose aspirin, increase of target INR to 3 to 4, or change to low molecular weight heparin may be considered (114).

Antiphospholipid syndrome presenting as arterial ischemia. The Antiphospholipid Antibodies and Stroke Study (APASS), a prospective cohort study within the Warfarin vs. Aspirin Recurrent Stroke Study (WARSS), a randomized, double-blind trial failed to demonstrate superiority of warfarin to 325 mg of aspirin in patients with a previous ischemic stroke and antiphospholipid antibodies.

The APASS study was limited by diagnosis of the antiphospholipid syndrome based on a single test and lack of patients with high-titer positivity (74).

A systematic review of 16 studies found that patients with stroke and one reading of antiphospholipid test had no increased risk compared to those without antiphospholipids (105).

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 (68). For those who meet the antiphospholipid syndrome criteria, anticoagulation with a target international normalized ratio of 2 to 3 is recommended (69; 105; 68; 114).

Antiphospholipid syndrome presenting with recurrent events. Retrospective data suggest that recurring thromboembolism despite INR of 2 to 3, may benefit from increasing target INR to greater than 3.0, as mortality is higher due to recurrent thrombosis than bleeding (102; 69; 105; 28).

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 (34). Additionally, the Warfarin in the Anti-Phospholipid Syndrome (WAPS) trial failed to demonstrate superiority of high-intensity warfarin treatment compared to medium-intensity anticoagulation (52). Nevertheless, increasing the target international normalized ratio to 3 to 4, adding low-dose aspirin, or switching to lower molecular weight heparin was suggested (114). The risk of hemorrhagic complications of such approach may be higher with combination therapy (89).

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.

Novel oral anticoagulants for thrombotic prophylaxis. 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. They have already been approved by FDA for several clinical indications. However, inadequate evidence exists on their use in patients with antiphospholipid syndrome (05).

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 two-fold increase in thrombin potential in patients receiving rivaroxaban (33). 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. Criticisms of this trial include exclusion of high-risk patients and relatively short period of follow-up (33). A subsequent trial failed to show noninferiority of rivaroxaban compared to warfarin in patients with thrombotic antiphospholipid syndrome. The risk of recurrent thrombosis was increased in the rivaroxaban arm who had arterial thrombosis, livedo racemose, or antiphospholipid syndrome-related cardiac valvular lesions (87).

The Trial on Rivaroxaban in Anti-Phospholipid Syndrome (TRAPS), which compares rivaroxaban with standard-intensity warfarin in patients with triple positive aPL antibodies, was prematurely stopped because all thrombotic events occurred in the rivaroxaban arm in triple-positive patients (91).

Another randomized trial comparing apixaban with warfarin was stopped prematurely after stroke occurred in 6 of 23 patients treated with apixaban and in 0 out of 25 of the patients enrolled in the warfarin arm (122).

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 being 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 (41).

Moreover, a metaanalysis of 282 patients treated with DOACs and 294 treated with warfarin showed that there was no increased recurrent thrombosis in patients treated with DOACS. Although the risk of venous thrombosis was not elevated in the DOACs treated patients, the risk of recurrent arterial thrombosis was increased (42).

More randomized controlled trials regarding the potential role of the novel oral anticoagulants in patients with the antiphospholipid syndrome may provide additional information. However, 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 (73).

Other treatments. Hydroxychloroquine is often added to the regimen of patients with antiphospholipid syndrome associated with systemic lupus erythematosus (104; 103). A single center study of 144 patients with systemic lupus erythematosus found that hydroxychloroquine prevented thrombotic events in patients with and without aPL antibodies (115). However, hydroxychloroquine had no independent protective effect in a metaanalysis of 497 subjects (06).

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:

• Cancer (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, in the absence of these factors, particularly in children or adults younger than 45 years of age, should prompt investigations for antiphospholipid syndrome. Other causes for this clinical presentation must be part of the work up and include:

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

Arterial and venous thromboses. The following conditions 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

Elevated aPTT may occur in clotting factor deficiency (factors VIII, IX, XI, and XII), disseminated intravascular coagulation, dysfibrinogenemia, and hyperfibrinogenemia. However, unlike in antiphospholipid syndrome, addition of normal plasma to patient’s plasma often corrects the elevated aPTT.

Obstetric complications. Recurrent fetal loss due to paternal or maternal chromosomal disorders, or maternal reproductive system anatomic abnormalities occurs 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.

Diagnostic workup

	• Antiphospholipid antibodies may occur in asymptomatic persons and decline with time.
	• At least one clinical and one laboratory criteria are needed for diagnosis of antiphospholipid syndrome.
	• The clinical criteria include arterial and/or venous thrombosis and/or obstetrical complication.
	• All three antiphospholipid antibodies should be tested: anticardiolipin, lupus anticoagulant, and anti-β2GPI.
	•The antiphospholipid antibody titer should be moderate or high on repeated testing.

The diagnostic criteria for antiphospholipid syndrome were revised in 2006 (81; 49). 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 imaging or histopathology should confirm this. 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 (11; 55).

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 result may become false positive under influence of warfarin, heparin, and direct oral anticoagulants.
	• 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.

Lupus anticoagulant testing has several stages: screening, mixing study, and confirmation.

Screening for lupus anticoagulant. If aPTT and/or dilute Russell viper venom time (dRVVT) are normal, lupus anticoagulant is ruled out. If they are prolonged, the patient’s plasma is mixed with normal plasma. Full correction of prolongation excludes lupus anticoagulant; coagulation factor deficiency may be the cause. Lack of correction requires confirmation with addition of phospholipid. If aPTT/dRVVT correct significantly, lupus anticoagulant is confirmed; if they are still significantly prolonged, consider an inhibitor.

Risk stratification is based on the antiphospholipid profile. High-risk antiphospholipid profile is characterized by detection of lupus anticoagulant on two or more occasions at least 12 weeks apart, or of double (any combination of lupus anticoagulant, anticardiolipin antibodies, or anti-β2GPI) or triple (all three 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 (103).

Management

	• Acute thrombosis is treated with thrombolytics.
	• Association with vasculitis requires consideration of immunosuppression.
	• Catastrophic antiphospholipid syndrome requires multiple approaches, including anticoagulation, immunosuppression, and plasma exchange or IVIG.
	• Direct oral anticoagulants are less effective than warfarin, especially in patients with high-risk (triple antibodies).
	• Rivaroxaban may be used if warfarin treatment is not practical but is less effective in high-risk patients.

Acute treatment. Arterial or venous thrombosis should be treated with intravenous thrombolytics, depending on the circulation involved as well as the standard recommendation for that organ system.

Association of antiphospholipid syndrome with systemic vasculitis is rare. Some manifestations such as livedo reticularis and retinal vasculitis are attributed to vasculitis. Differentiation between vasculitis and thrombosis helps in choosing antithrombotic versus immunosuppressive therapy (70).

Treatment of catastrophic antiphospholipid syndrome. Catastrophic antiphospholipid syndrome has a mortality rate of 50% and requires ICU care. The “triple therapy” is a combination of anticoagulation, corticosteroids, and plasma exchange or IVIG is recommended (21). Cyclophosphamide improves outcome only in patients who also have systemic lupus erythematosus (12). Rituximab and eculizumab may have a role in catastrophic antiphospholipid syndrome management (48; 13).

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 changes 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 (38). 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 (95).