Clinical manifestations

Presentation and course

Antiphospholipid syndrome is primarily a disorder of hypercoagulable state and systemic thrombosis, which can be both arterial and venous. Most of its 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 secondary to antiphospholipid antibody syndrome (50). Stroke (19.8%) and transient ischemic attacks (11.1%) were among the most common manifestations in the “Euro-Phospholipid” cohort (19). Screening for antiphospholipid antibodies is recommended in young adults (< 50 years) with ischemic stroke (54). Cerebral venous sinus thrombosis is also a well-recognized complication (Deschiens et al 1996; Carhuapoma et al 1997; 26). Cerebral vascular thrombosis, atheroemboli from extracranial large vessels, and cardiac emboli from valvular vegetations, endocarditis, and intracardiac thrombi are potential underlying pathophysiological mechanisms involved.

The presence of antiphospholipid antibodies has been frequently associated with autoimmune chorea (22; 73). Other reported neurologic associations include migraine headaches, encephalopathy, seizures, dementia, Guillain-Barre syndrome, psychosis, and transverse myelopathy (Muscal and Brey 2008; 75). Antiplatelets and anticoagulation are only recommended for cerebrovascular disease and venous sinus thrombosis.

Other neurologic manifestations are seizures, dementia, cognitive dysfunction, chorea, migraine, psychosis, and demyelinating disease (51).

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 valvular abnormalities (stenosis or regurgitation) have frequently been documented in both systemic lupus erythematous and antiphospholipid syndrome. Patients with myocardial infarction with nonobstructive coronary arteries exhibit high prevalence of thrombophilia including antiphospholipid antibody syndrome (96). However, whether antiphospholipid syndrome is primarily causative hasn’t been well established.

Dermatologic. Livedo reticularis and livedo vasculitis are the best described 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, thrombosis of 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 an end point or manifestations of the thrombotic events described above.

Pulmonary. Most common manifestations are thrombotic and 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 hematologic manifestation, which was initially used as a diagnostic criterion, is thrombocytopenia. This is secondary to antiphospholipid antibody-related splenic sequestration; however, it is rarely serious enough to lead to bleeding complications. Similar mechanisms underlie other hematologic manifestations, like 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. Common arterial presentations include thrombosis of aorta, axillary, ileofemoral, and popliteal arteries. Venous thromboses are especially common in deep venous thrombosis of the leg. Other venous systems include adrenal vein and inferior venous cava.

Obstetric complications. Obstetric complications of antiphospholipid syndrome are well described and are the cornerstone of diagnostic criteria involving its diagnosis in women of childbearing age. These include 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. Maternal thrombocytopenia is a relatively rare manifestation of antiphospholipid syndrome and has also been reported.

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, in less than 1% of antiphospholipid syndrome patients, thrombotic manifestations involving multiple organ systems can be the presentation. When it involves three or more systems, it is defined as catastrophic antiphospholipid syndrome (CAPS). The criteria for the diagnosis of CAPS are as follows (07; 23):

Patients with antiphospholipid syndrome often present with respiratory failure, stroke, renal impairment, and cutaneous manifestations and follow a fulminant course. Most often, the involved systems include renal, pulmonary, neurologic, cardiac, and cutaneous (04). Thrombosis of the microvasculature of these systems is the unifying pathological feature (08). Precipitating events include 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 of antiphospholipid syndrome that is associated with small vessel occlusion in at least one organ or tissue, along with involvement of two or more organs or systems (05). 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 (05; Asherson and 19). 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 (Asherson and 19). 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. Arterial thrombosis is associated with a recurrence rate as high as 90%, whereas venous thrombosis can increase this risk of recurrence to 70% (86). The chances of a patient with recurrent thrombosis are dependent on anticoagulation and target INR achievement, but patients with refractory antiphospholipid syndrome usually have a very grim prognosis. Also, it is important to screen women of childbearing age with arterial or venous events for antiphospholipid syndrome because such an index event marks an 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 (07; 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 (85).

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. She was found to have 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 aCL antibody, which was strongly positive (> 99 percentile). Patient had negative LAC 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. On review of her medical history, it was found that she had 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 was also found to have 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 aCL, 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 antiphospholipid syndrome. 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 reported association is with systemic lupus erythematous. Other underlying causes include infections (mycoplasma, malaria, Lyme, etc.) or drugs (interferons, sulfonamides, etc.).

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

For thrombosis to occur intravascularly, the index event is usually injury to the endothelium, which then results in the release of tissue factor that activates the intrinsic pathway. Thereafter, there is a cascade of prothrombotic upregulation involving clotting factors and platelets, resulting in formation of a vascular clot. At the same time, there is downregulation of the anticoagulant mechanisms. The pathogenetic basis of thrombosis in antiphospholipid syndrome is believed to involve all three of these events in such a way that the body mimics a state of vascular injury predisposing to vascular thrombosis.

Endothelial activation. Although the role of antiphospholipid antibody in the activation of endothelial cells is well established, the exact mechanism is not clear (100). β2GpI binds with high affinity to annexin A2, an endothelial receptor (102). This interaction is considered to pay a key role in endothelial cell activation (102). Annexin may be induced by oxidative stress (63). Several other receptors have been identified besides annexin A2 (100).

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. Exposure to an activated endothelium results in platelet activation. However, antiphospholipids play a distinct role in magnifying this activation process. The GpIb subunit of the GPIb/IX/V receptor on the platelet surface interacts with the anti-β2GpI antibody, leading to thromboxane production and the activation of the phosphoinositide-3 kinase/Akt pathway (94). This pathway contributes to increased thromboxane production, which, in turn, contributes to platelet aggregation and activation.

Complement. Complement activation as a possible prothrombotic mechanism is suggested by increased complement production in patients with acute cerebrovascular events compared with patients suffering from non-antiphospholipid syndrome–related cerebral ischemia (31). This appears to be specifically related to complement factors C5 and C6, and appears to be strongly associated with the presence of IgG-type antiphospholipids compared to the IgM or IgA subclasses (42).

Dysregulation of fibrinolysis. Fibrin cross-linkage is an important step in clot organization and is often countered by tissue plasminogen activator (tPA). The latter is activated to plasmin and aids in fibrinolysis and clot disruption. Although not involved in mainstream diagnosis, antiphospholipid syndrome is often associated with other antibodies like anti-annexin 2 (anti-A2), anti-tPA, and antiplasmin (30; 101; 25). Annexin 2 is involved in colocalizing endothelial tPA and plasminogen in a physiological state, resulting in plasmin production (62). The presence of these antibodies disrupts this interaction, resulting in disruption of fibrinolysis.

Anticoagulant downregulation.

Activated protein C inhibition. The major anticoagulant pathway in the body involves protein C and protein S. Protein C is activated by an activated endothelium and subserves its anticoagulant function by binding and inactivating factor Va and VIIIa. In vitro studies have revealed that the β2GpI-anti β2GpI complex binds to components of activated protein C (APC) complex (90). Thus, putatively, it results in a competitive inhibition of factor Va and VIIIa by saturated binding sites on APC.

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 by binding to it, and this may be the basis of placental thrombosis and fetal loss in patients with obstetric antiphospholipid syndrome (81; 82). Other mechanisms include inhibition of activated factor X and tissue factor pathway (91; 43).

A now widely accepted concept in the pathogenesis of antiphospholipid syndrome is the “2-hit hypothesis” (95; 49). The presence of antiphospholipids induces a thrombophilic state, 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 (84; 95; 59). This has also been documented in vitro as 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 (66).

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 (Petri 2000; 13; 14). However, asymptomatic patients with positive antiphospholipid antibodies have a 0% to 4% risk of thrombosis (47). Most of these asymptomatic patients have antibodies secondary to exposure to infections, malignancies, or drugs. These antibodies are usually transient and present at low levels (93). The commonest antibodies found are aCL, followed by LAC and anti-β2GPI (12). Because these antibodies can be present in such transient, low levels, the diagnostic criteria of antiphospholipid syndrome requires them to be present at certain higher levels (67).

The titers of antiphospholipids are much higher in patients with other autoimmune diseases. Systemic lupus erythematous patients are also at a higher risk of developing antiphospholipid syndrome, with 20-year risks ranging from 30% to 70% (72). Antiphospholipid antibodies associated with other diseases are at a higher risk of thrombosis compared to patients who have antiphospholipids in the absence of an underlying primary disease (60). Common underlying primary disorders include systemic lupus erythematous, rheumatoid arthritis, malignancies, and infections (syphilis, hepatitis C, HIV, cytomegalovirus, tuberculosis, leprosy, etc.) (83; 17; 98).

There are few longitudinal and demographic studies of antiphospholipid syndrome because they are difficult to conduct. The prevalence of antiphospholipids has been reported to be as low as 2% in Afro-Caribbean countries and as high as 51% in some Asian countries (14). It also appears that Caucasians are at a higher risk of thrombosis compared to Chinese patients (68). Data for other population bases are lacking. The antiphospholipids have also been associated with certain haplotypes like HLA-DR4, HLA-DR7, HLA-DRw53, and HLA-DQB1-0302 (92). 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 presenting as a deep venous thrombosis (19). The frequency of antiphospholipids in patients presenting with deep venous thrombosis ranges from 5% to 30%. The most common obstetric complication is fetal loss. The most common obstetric presentation is fetal loss. Other pregnancy-related manifestations like preeclampsia, HELLP syndrome, intrauterine growth restriction (IUGR), and preterm labor can happen in up to 35% of pregnant patients with antiphospholipid syndrome (21). Arterial thrombosis accounts for 30% of all thromboses associated with antiphospholipid syndrome (41). Of these presentations, the commonest ones are transient ischemic attacks/strokes followed by coronary and peripheral arterial system involvement (50). Although there have been suggestions of antiphospholipids interacting with other prothrombotic risk factors like patent foramen ovale in increasing the incidence of stroke, a study found no association between the antiphospholipid, patent foramen ovale, and stroke incidence (79).

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 aCL, anti-β2GpI, LAC). The APLASA study was a randomized controlled trial that studied the efficacy of low-dose (81 mg) aspirin in primary thrombosis prevention as compared to a placebo (36). The trial was done in asymptomatic persistently positive antiphospholipid antibody patients, and it failed to find any superiority of aspirin in reducing these events. The study was limited by excluding high-risk patients (high titer, obstetric antiphospholipid syndrome) and including certain low-risk groups, like those with IgA aCL. Also, most thrombotic events in both groups were associated with other prothrombotic factors (99).

More recently, a patient-level data analysis of five international cohort studies investigating whether continuous treatment with low-dose aspirin has a significant protective effect on the risk of first thrombosis among patients with antiphospholipid antibodies revealed a protective effect of aspirin against arterial thrombosis for systemic lupus erythematosus and asymptomatic antiphospholipid carriers. Limitations of this analysis include exclusion of a number of potentially relevant studies due to inability to obtain individual patient data and possible confounding by unmeasured factors such as oral contraceptive use and inherited thrombophilia (02).

The ALIWAPAS study, a prospective, multicenter, randomized, open, controlled trial further compared treatment with low-dose aspirin to treatment with a combination of low-dose aspirin and low-intensity warfarin in primary thrombosis prevention in patients who were antiphospholipid antibody positive and had systemic lupus erythematosus, or obstetric morbidity, or both. There were no differences in number of thrombotic events in the two treatment groups and more episodes of bleeding in the group treated with warfarin and aspirin, making the combination treatment significantly less safe and not as acceptable as aspirin alone (29).

Given the results of these studies and results from certain observational studies, most physicians recommend aspirin for patients who are at high risk at developing thrombosis (high titers). Hydroxychloroquine is often added to the regimen of patients with secondary antiphospholipid syndrome associated with SLE (76; 88; 87).

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 (66). Thus, it becomes imperative to maximize the medical management of comorbidities in these patients. Chief among these is avoidance of cigarette smoking as well as cessation of contraceptive pills. Aggressive control of hypertension, hyperlipidemia, and diabetes are also cornerstones of this preventive strategy (99; 87). Lastly, high-risk situations like surgery and long-distance flight can be managed using subcutaneous heparin (99) or low molecular weight heparin (87).

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:

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:

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

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 six weeks) or mid- (six to nine weeks) fetal period. Antiphospholipid syndrome typically causes fetal loss after nine 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

In 2006, Miyakis and colleagues proposed a revision to the diagnostic criteria for antiphospholipid syndrome (67; 39). 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. These chiefly include the following:

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

Management

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

Prophylaxis. Primary prophylaxis in antiphospholipid-positive asymptomatic individuals usually involves prevention of other thrombotic risk factors. Although not entirely conclusive, the 13th International Congress on Antiphospholipid Antibodies did recommend low-dose aspirin in patients with high antiphospholipid antibody titers or in women of childbearing age who are antiphospholipid positive (99; 87). The addition of hydroxychloroquine is recommended for those patients who also have systemic lupus erythematosus (87). However, the prophylaxis differs for patients who have had previous index events. Thromboprophylaxis usually depends on the type and frequency of index events.

Antiphospholipid syndrome presenting as venous thrombosis. There is evidence that patients presenting with venous thrombosis will have recurrent venous thrombosis in 70% of cases (86). This rate is significantly reduced with long-term anticoagulation. Brief periods of anticoagulation often result in post-stoppage thrombosis, making the case for lifelong anticoagulation. Although historically patients were put on high intensity (target INR: 3.0 to 4.0), evidence has shown that the high doses can result in high incidence of hemorrhagic complications without offering significant reduction in risk of thrombosis (28). Therefore, patients with index venous thrombotic events are treated with warfarin and have a target INR of 2.0 to 3.0 (99; 87).

Antiphospholipid syndrome presenting as arterial ischemia. Cerebral ischemia is the commonest presentation of arterial ischemia. Ninety percent of cases with arterial strokes can have recurrence (86). Data regarding appropriate therapy following index stroke in antiphospholipid syndrome are surprisingly limited. Most studies with medium-intensity prophylaxis for thrombosis involve venous thrombosis (99). To date, there has been only one prospective randomized control trial, the Antiphospholipid Antibodies and Stroke Study (APASS), compared the use of aspirin versus warfarin in patients with a previous ischemic stroke (61). The study did not find any significant decrease in incidence of recurrent stroke in the use of warfarin over aspirin. However, the study did have some limitations as the diagnosis of the antiphospholipid disorder was based on a single test. Additionally, it did not specifically test individuals with high-titer positivity as the sample size was too small for this analysis.

The American Stroke Association guidelines recommend antiplatelet monotherapy for patients with cryptogenic ischemic stroke or transient ischemic attacks in the presence of antiphospholipid antibodies who do not meet the criteria for antiphospholipid syndrome (55). The guidelines recommend antiplatelet therapy for patients who meet the criteria for antiphospholipid syndrome but in whom anticoagulation is not yet begun (55), and the 13th International Congress on Antiphospholipid Antibodies recommendations include antiplatelet therapy for a first noncardioembolic cerebral arterial event in patients with a low-risk antiphospholipid antibody profile and the presence of reversible trigger factors who do not have systemic lupus erythematosus (87). Anticoagulation is recommended for patients with ischemic stroke or transient ischemic attacks who fulfill the criteria for antiphospholipid syndrome; those with any other manifestations such as venous thrombosis; as well as those with recurrent ischemic strokes (86; 56; 89; 99; 55). Others, including the 13th International Congress on Antiphospholipid Antibodies, have also recommended high-intensity anticoagulation in patients with arterial strokes. Evidence in support of high-intensity anticoagulation includes the higher risk of recurrence at INR 2.0 to 3.0 than INR greater than 3.0 and the higher frequency of death due to recurrent thrombosis than due to bleeding (24), but the high incidence of hemorrhagic complications with this dose may severely limit its application or need (86; 89; 99; 44; 87).

Antiphospholipid syndrome presenting with recurrent events. In patients for whom secondary thromboprophylaxis fails with medium intensity anticoagulation (INR 2.0 to 3.0), most evidence suggests increasing the INR goal to 3.0 to 4.0 (86; 56; 89; 99). Others recommend switching anticoagulation to lower molecular weight heparin (LMWH) or unfractionated heparin, or using combination of aspirin and warfarin (Muscal and Brey 2010; 87; 74). The risk of hemorrhagic complications may be higher with the combination therapy (74). Hydroxychloroquine or statins have also been suggested as alternative therapies for individuals with recurrent thrombosis, fluctuating INR levels, major bleeding, or a high risk for major bleeding (87).

Antiphospholipid syndrome presenting with obstetric complications. Recommendations for obstetric antiphospholipid syndrome patients vary on the type of presentation.

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 (58).

Treatment of CAPS. CAPS is usually a life-threatening presentation that often requires ICU care and rapid control of microvascular thrombosis as mortality can be as high as 50%. Anticoagulation is frequently used in this setting as first-line treatment. Corticosteroids should also be considered as first-line treatment, unless there is any specific contraindication (20). Plasma exchange also improves outcomes in patients with CAPS and is used in most patients (16). The combination of these therapeutic options with or without IVIG may achieve the best outcomes (16). The use of cyclophosphamide improves outcomes only in the patients who also have systemic lupus erythematous (10). Rituximab and eculizumab may have a role in CAPS management (37; 11).

Novel oral anticoagulants for thrombotic prophylaxis in antiphospholipid syndrome. There is interest in the possible use of novel oral anticoagulants in patients with antiphospholipid syndrome because of perceived advantages of these medications 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, but inadequate evidence exists on their use in patients with antiphospholipid syndrome (01). At present data from only one randomized controlled trial, Rivaroxaban Versus Warfarin to Treat Patients with Thrombotic Antiphospholipid Syndrome with or without Systemic Lupus Erythematosus (RAPS) is available. This open-label phase 2/3 noninferiority trial measured the mean percentage change of endogenous thrombin potential before and after the introduction of rivaroxaban. The trial failed to reach noninferiority due to a 2-fold increase in thrombin potential in patients receiving rivaroxaban, but 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 because no clinical event occurred in either treatment group (27). Criticisms of this trial include exclusion of high-risk patients and relatively short period of follow-up. 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. 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 (34).

Special considerations

Pregnancy

Pregnancy-related morbidity has always been the cornerstone of diagnosis of antiphospholipid syndrome in women of childbearing age. The clinical criteria for diagnosis of obstetric antiphospholipid syndrome include recurrent fetal loss, early fetal loss, and late pregnancy complications like IUGR, preterm labor, or preeclampsia (09; 45).

Epidemiological studies of these presentations reveal that up to 25% of recurrent miscarriages can be attributed to antiphospholipid syndrome (33; 45). According to one study, the rate of early fetal loss in women with antiphospholipid syndrome was as high as 35.4%, whereas late fetal loss was as high as 16.9% (22). Another study reported the incidence of premature births and IUGR at 35% and 13.7%, respectively, in patients with antiphospholipid syndrome (97).

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

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 high incidence of fetal loss. This has been confirmed to high incidence by animal studies, where murine models inoculated with antiphospholipid antibodies caused early resorption of pregnancy (77; 45).

Treatment of obstetric antiphospholipid syndrome depends on the type of clinical presentation prior to the diagnosis of antiphospholipid syndrome in these patients. This has been discussed in detail in the Management section. Aspirin, or low-molecular weight heparin, or both are the cornerstones of therapy for obstetric antiphospholipid syndrome.

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 (32). 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 (80).