Antiphospholipid antibody syndrome …

Adrian Marchidann MD

Stroke & Vascular Disorders

Updated 10.29.2024
Released 01.02.2008
Expires For CME 10.29.2027

Antiphospholipid antibody syndrome

Author: Adrian Marchidann MD

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Editor: Steven R Levine MD

Antiphospholipid antibody syndrome

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Introduction

Overview

Antiphospholipid syndrome is a coagulopathy affecting multiple organ systems. It should be suspected in young patients, presenting with unexplained venous thrombosis, arterial infarcts, and miscarriages. Catastrophic antiphospholipid syndrome is a fulminant form of widespread coagulopathy. The cornerstone of therapy is anticoagulation. In this article, the authors comprehensively review the disorder, including clinical manifestations, pathogenesis, and management.

Key points

	• Antiphospholipid syndrome is a thrombo-inflammatory state associated with persistent antiphospholipid antibodies.
	• Cerebral arteries are a common site of thrombosis.
	• Screening for antiphospholipid antibodies is recommended in young patients presenting with unexplained ischemic strokes or recurrent miscarriages.
	• Catastrophic antiphospholipid syndrome is a rare, life-threatening, presentation with simultaneous involvement of multiple organ systems.
	• Antiplatelets and anticoagulation are the mainstay treatments for thrombotic complications, with a potential role of various immunosuppressants in some complicated cases.

Historical note and terminology

Positive screening testing for syphilis is often associated with other infections (Moore and Mohr 1952). Individuals who test positive for syphilis occasionally develop systemic lupus erythematosus (84). Moreover, patients with systemic lupus erythematosus may have circulating antibodies associated with thromboembolism (19). These antibodies were named “lupus anticoagulant” because the activated partial thromboplastin time (aPTT) was elevated (51). Later, lupus anticoagulant was linked to recurrent abortion (86).

Antiphospholipid syndrome is associated with recurrent arterial or venous thrombosis, spontaneous abortion, and thrombocytopenia in patients with moderate to high titers of antiphospholipid antibodies measured twice at 12 weeks apart. Antiphospholipid syndrome can be primary in the absence of autoimmune disorders and secondary if associated with autoimmune disorders.

Clinical manifestations

Presentation and course

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

Nervous system. Arterial thrombosis in antiphospholipid syndrome occurs most commonly in the cerebral circulation (61). Stroke and transient ischemic attack were among the most common manifestations in the “Euro-Phospholipid” cohort (25). 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 with ischemic stroke (60).

Cerebral venous sinus thrombosis is another complication of antiphospholipid syndrome (33). 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 (68).

Other associated neurologic conditions associated with antiphospholipids include autoimmune chorea, migraine headaches, encephalopathy, seizures, dementia, Guillain-Barre syndrome, psychosis, and transverse myelopathy (27; 91; 89; 63).

Heart. Mural thrombosis, microthrombi, and coronary artery disease often occur in patients with antiphospholipid syndrome. Noninfectious endocarditis, valvular vegetations, stenosis, and regurgitation have been associated with systemic lupus erythematosus and antiphospholipid syndrome. Approximately 15.5% of patients with myocardial infarction with nonobstructive coronary arteries had antiphospholipid syndrome (114).

Skin. Livedo reticularis and livedo vasculitis should raise the suspicion of antiphospholipid syndrome. Other manifestations include thrombophlebitis, ulcerations, digital gangrenes, and splinter-hemorrhages.

Kidney. Antiphospholipid-associated nephropathy is a thrombotic microangiopathy involving arterioles and glomerular capillaries and may result in acute and chronic renal failure, proteinuria, and hematuria.

Lungs. Pulmonary embolism and pulmonary arterial thrombosis are the most common manifestations of antiphospholipid syndrome. Non-thrombotic vasculopathy and pulmonary hypertension have been reported as well.

Gastrointestinal system. Antiphospholipid syndrome is associated with 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 most common hematologic feature of antiphospholipid syndrome is thrombocytopenia due to splenic sequestration. This 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 of antiphospholipid syndrome include thrombosis of the aorta, axillary, ileo-femoral, and popliteal arteries. Venous thrombosis is common in the deep veins of the leg.

Obstetric complications. Antiphospholipid syndrome is responsible for 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, intrauterine growth retardation, and preterm delivery. Maternal thrombocytopenia occurs rarely.

Catastrophic antiphospholipid syndrome. Antiphospholipid syndrome typically presents as a single event involving one organ system. Although subsequent episodes may affect other systems, each episode is usually isolated to that system. However, less than 1% of antiphospholipid syndrome cases present with multiple organ thrombosis. The diagnostic criteria for catastrophic antiphospholipid syndrome include the following:

• Involvement of three or more organ systems
• Simultaneous onset or onset within 7 days in all organ systems
• Pathological evidence of thrombotic involvement of microvasculature
• Presence of antiphospholipid antibodies

The catastrophic antiphospholipid syndrome complications are respiratory failure, stroke, renal impairment, and cutaneous manifestations and follow a fulminant course (09; 07; 28).

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).

The 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 and distribution of vascular territory involved. The risk of recurrent thrombosis is 91% in the initial vascular type (103). Refractory antiphospholipid syndrome usually has 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 the catastrophic antiphospholipid syndrome as it can approach 50% mortality (09; 46).

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 (102).

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 a 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). The patient had negative lupus anticoagulant and β2 glycoprotein antibody.

Clinical vignette 2: secondary antiphospholipid syndrome. A 35-year-old woman presented with possible seizures during sleep. She had several miscarriages. The first one, 5 years before her current presentation, occurred at 12 weeks. The 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 rapid plasma reagin and transiently elevated activated partial thromboplastin time. A 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 may be idiopathic or the result of an underlying process.
	• The mechanism of antiphospholipid syndrome is an imbalance between coagulation and anticoagulation.
	• Multiple hemostatic processes 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 in the absence of an underlying disease. 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. Antiphospholipid syndrome tilts the balance towards excessive coagulation.

Prothrombotic upregulation. Thrombosis associated with anticardiolipin antibodies was described as antiphospholipid syndrome (65). Anticardiolipin antibodies from patients with systemic lupus erythematosus require beta2-glycoprotein1 (bet2GPI) to bind to cardiolipin. Beta2GPI is an inhibitor of platelet activation and coagulation (57; 79; 66). Lupus anticoagulant, anticardiolipin, and anti-beta2GPI are considered pathogenic within the clinical spectrum of antiphospholipid syndrome.

Endothelial activation. Endothelial injury releases the tissue factor that activates the intrinsic coagulation pathway. Mannose-binding lectin binds to endothelial beta2GPI, activates the complement, and stimulates thrombin generation. Surface receptors for beta2GPI and anti-beta2GPI include apolipoprotein E receptor 2 (apoER2) and the complex annexin A2 and TLR4. Activation of p38 MAPK upregulates the tissue factor (119). Migration of NF-KB from the cytoplasm into the nucleus enhances the expression of tissue factor and cell adhesion molecules (44).

At the same time, endothelial activation decreases nitric oxide synthesis (05).

Annexin A2 is a tPA endothelial receptor (128). Endothelial priming with TNF-alpha amplifies thrombin generation (45). During pregnancy, β2GPI binds to the uterine endothelial cells and trophoblast. Fetal loss was associated with C3 and C9 deposition (03).

Tissue factor activity upregulation. Antiphospholipid antibodies enhance the production of the tissue factor by the endothelial cells (94). Additionally, inhibition of tissue factor pathway inhibitor type 1 (TFPI) by IgG from patients with lupus stimulates thrombin generation (01; 76).

Platelet activation. Binding by β2GPI on the surface of unstimulated platelets is limited. Once exposed to stress or thrombin, platelets become activated (120). 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 (110). Thromboxane contributes to platelet aggregation and activation. Additionally, the platelets exposed to antiphospholipid antibodies increase the expression of GP IIb/IIIa and GPIIIa receptors (48). Healthy platelets in contact with calcium, prothrombin, and anti-GPI become activated. This may explain why vitamin K antagonists are more effective anticoagulants than factor Xa (32).

Complement activation. Complement activation contributes to thrombosis (38). This appears to be related to C5 and C6 and is strongly associated with IgG-type antiphospholipid antibodies (54).

Neutrophil activation. The presence of antiphospholipid antibodies, while necessary, does not trigger antiphospholipid syndrome. In the presence of lipopolysaccharides, the activation of neutrophils by antiphospholipid antibodies was significantly increased through the toll-like receptor, TLR-4 (62). Additionally, the release of neutrophil extracellular traps (NETosis) by antibodies anti-β2GPI also triggers thrombosis (80). Neutrophil extracellular traps are webs of extracellular chromatin and antimicrobial proteins resulting from neutrophil death (20). 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 (100). At the same time, the neutrophil extracellular trap promotes thrombin generation (124).

Monocyte activation. The monocytes increase the expression of tissue factor on their surface and trigger thrombosis (78).

Inhibition of fibrinolysis. Thrombosis is disrupted by tissue plasminogen activator (tPA). The annexin 2 (A2) complex, a cell surface receptor for tPA, facilitates the generation of plasmin and clot dissolution (64; 77). Antiphospholipid syndrome is often associated with other antibodies against annexin 2, tPA, and plasmin (37; 125; 30). β2GPI is a cofactor for tPA-mediated cleavage of plasminogen. Therefore, anti-β2GPI antibodies prevent plasmin formation (21). Moreover, plasminogen activator inhibitor-1 is upregulated (113).

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 the activated protein C (APC) complex, thus inhibiting its anticoagulation activity (107).

Prevention of antithrombin activation. Full activation of antithrombin is prevented by the antiphospholipid antibodies with affinity for heparan sulfate, an endothelial anticoagulation modulator. These antibodies inhibit the heparin-accelerated binding of antithrombin III to thrombin (111). In addition, antibodies against factors II, IX, and Xa prevent their inhibition by thrombin (67; 127; 126).

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 (97; 98). Inhibition of activated factor X and tissue factor pathway also plays a role in coagulopathy (108; 55).

The “2-hit hypothesis” suggests that the mere presence of antiphospholipid antibodies, while necessary, is enough to cause thrombosis (112; 59). 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 (101; 112; 72). In vitro, a lipopolysaccharide was required to trigger thrombosis in rats with anti-β2GPI IgG (54). This hypothesis only applies to vascular complications and does not entirely describe the obstetric manifestations of the disease (81).

Obstetric complications are thought to result from vascular thrombosis (24).

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 (121). Complement activation in the placenta mediates the inflammatory response. Alteration of trophoblast differentiation and maturation, direct cellular damage, and apoptosis contribute to fetal loss. Mice inoculated with antiphospholipids experienced early resorption of pregnancy (93; 56). 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 (18). Approximately 60% of patients have rare germline variants of the complement regulatory gene compared to 23.3% of normal controls (31).

The occlusive vasculopathy in chronic form is characterized by progressive expansion of intima due to endothelial cell proliferation (04). Additional factors are vascular smooth proliferation and deposition of proteoglycan-rich extracellular matrix (04).

The precipitating events of catastrophic antiphospholipid syndrome are infections, surgery, or drugs. Thrombosis of the microvasculature of these systems is the unifying pathological feature. Disseminated intravascular coagulation, an unusual manifestation of isolated antiphospholipid syndrome, has frequently been associated with catastrophic antiphospholipid syndrome, probably secondary to widespread thrombotic activation (10).

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 syndrome is 40 to 50 per 100,000 and the annual incidence is 1 to 2 per 100,000 (41). The antiphospholipid antibodies alone do not always trigger a clinical syndrome. Between 1% to 10% of the asymptomatic population test positive for antiphospholipid antibodies, and the titers usually decline with time (122; 17). 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 (16).

Asymptomatic patients with positive antibodies have a 0% to 4% risk of thrombosis (58). Most antibodies are anticardiolipin, followed by lupus anticoagulant and anti-β2GPI (15). They result from exposure to infections, malignancies, or drugs, and are usually present transiently at low levels (109). Diagnosis of antiphospholipid syndrome requires persistent, moderate to high levels of these antibodies (82).

The risk of thrombosis is higher when the antibodies are associated with a primary disease (73). Common underlying primary disorders include systemic lupus erythematous, rheumatoid arthritis, malignancies, and infections like syphilis, hepatitis C, HIV, cytomegalovirus, tuberculosis, or leprosy (99; 23; 118). For example, over 20 years, the risk of developing antiphospholipid syndrome is between 30% to 70% in patients with systemic lupus erythematous (87).

The prevalence of antiphospholipid antibodies was as low as 2% in Afro-Caribbean countries and as high as 51% in some Asian countries (17). Caucasians seem to have a higher risk of thrombosis compared to Chinese patients (83).

Deep venous thrombosis is the most common presentation of antiphospholipid syndrome (25). 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 (52; 61). Although interaction of antiphospholipid antibodies with patent foramen ovale was suspected, no association between the antiphospholipid, patent foramen ovale, and stroke incidence was found (95).

Fetal loss is the most common obstetric complication of antiphospholipid syndrome, which is responsible to 25% of recurrent miscarriages (40; 56). 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 (27; 26).

Intrauterine growth retardation was found in 13.7% of women with antiphospholipid syndrome (117)

Prevention

	• A moderate to high titer antibody warrants avoidance of estrogen supplements and active perioperative thromboprophylaxis.
	• Low-dose aspirin prevents the 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 a target international normalized ratio (INR) of 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 an INR of 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. Thrombosis in asymptomatic individuals with antiphospholipid antibodies correlates with other risk factors. This is relevant given the “two-hit” pathogenetic theory of thrombosis development (81). Physical exercise, avoidance of smoking while taking oral contraceptives, and treatment of hypertension, hyperlipidemia, and diabetes are useful. High-risk conditions 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 (47).

In an analysis of five international cohort studies, low-dose aspirin protects against a first arterial, but not venous, thrombosis in asymptomatic carriers and in patients with systemic lupus erythematosus (06).

The ALIWAPAS study was a prospective, multicenter, randomized, open, controlled trial in patients with antiphospholipid antibodies and systemic lupus erythematosus or obstetric morbidity, or both (36). Low-intensity warfarin addition to low-dose aspirin did not provide additional protection against a first thrombosis. Moreover, the combination increased the risk 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 the low-risk antiphospholipid profile and is recommended in the high-risk antiphospholipid profile. Nonpregnant women with a history of obstetric antiphospholipid syndrome only may be offered low-dose aspirin (115).

Antiphospholipid syndrome with venous thrombosis. Warfarin administration aiming at an international normalized ratio (INR) of 2 to 3 is preferred. Rivaroxaban is an alternative if maintaining a therapeutic INR is challenging or in cases of warfarin allergy or intolerance. However, rivaroxaban should be avoided in patients with triple antibody positivity (106).

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, the addition of low-dose aspirin, an increase of target INR to 3 to 4, or a change to low molecular weight heparin may be considered (115).

Antiphospholipid syndrome with 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 the superiority of warfarin to 325 mg of aspirin in patients with a previous ischemic stroke and antiphospholipid antibodies. One limitation of the APASS study was that the diagnosis was based on a single test and a lack of patients with high-titer positivity (75).

A systematic review of 16 studies found that patients with stroke and positive antiphospholipid antibody test had no increased risk compared to those who tested negative (106). A meta-analysis of 811 patients from eight studies found that compared to warfarin, DOAC prevents venous but not arterial strokes. Increasing the target INR or adding antiplatelets to warfarin does not reduce the risk of stroke but increases the risk of hemorrhagic complications (11).

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 (69). For those who meet the antiphospholipid syndrome criteria, anticoagulation with a target international normalized ratio of 2 to 3 is recommended (70; 106; 69; 115).

Antiphospholipid syndrome with recurrent thrombotic events. Retrospective data suggest that recurring thromboembolism despite INR of 2 to 3, may benefit from increasing the target INR above 3.0, as mortality is higher due to recurrent thrombosis than bleeding (103; 70; 106; 29).

However, in a randomized, double-blind clinical trial of 114 patients, high-intensity (target INR: 3.0 to 4.0) was not more effective than moderate-intensity anticoagulation (35). Additionally, the Warfarin in the Anti-Phospholipid Syndrome (WAPS) trial failed to demonstrate the superiority of warfarin at high compared to medium intensity (53). Nevertheless, increasing the target international normalized ratio to 3 to 4, adding low-dose aspirin, or switching to lower molecular weight heparin was suggested (115). The risk of hemorrhagic complications of such an approach may be higher with combination therapy (90).

Antiphospholipid syndrome 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. Newer oral anticoagulants, including direct thrombin inhibitors (dabigatran) and anti-factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban), have several advantages over warfarin. They have a predictable anticoagulant effect, do not require monitoring, and do not interact with foods, alcohol, and drugs.

Several clinical trials failed to demonstrate the non-inferiority of rivaroxaban compared to warfarin (34; 92). The risk of recurrent thrombosis was higher in the rivaroxaban arm, who had triple-positive antiphospholipid antibodies, arterial thrombosis, livedo racemose, or antiphospholipid syndrome–related cardiac valvular lesions (88). A study in Canada comparing rivaroxaban and warfarin was stopped due to failure to enroll sufficient patients (74). The randomized clinical trial comparing apixaban with warfarin was also stopped prematurely because stroke occurred in six of 23 patients treated with apixaban and in 0 of 25 patients enrolled in the warfarin arm (123).

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 (42). Moreover, a couple of meta-analyses comparing DOAC with warfarin revealed that although the risk of venous thrombosis was not elevated in the DOAC arm, arterial thrombosis was more frequent in the same arm (43; 02).

Other treatments. Hydroxychloroquine is often administered when the antiphospholipid syndrome is associated with systemic lupus erythematosus (105; 104). A single-center study of 144 patients with systemic lupus erythematosus found that hydroxychloroquine prevented thrombotic events in patients with and without antiphospholipid antibodies (116). However, hydroxychloroquine had no independent protective effect in a meta-analysis 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 best describes the possible differential diagnosis of antiphospholipid syndrome.

Hematological/vascular presentation. Antiphospholipid syndrome presents with thrombosis in both arterial and venous beds. However, because the first episodes are usually isolated, antiphospholipid syndrome should be considered in 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. Hypertension, diabetes, atherosclerosis, and cardioembolism cause most arterial infarctions. However, 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, the addition of normal plasma to the 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. Antiphospholipid syndrome should be considered when other risk factors of preeclampsia (maternal diabetes, early or late maternal age, history of gestational hypertension) have been ruled out.

Diagnostic workup

	• Antiphospholipid antibodies may be detected in asymptomatic individuals and change with time.
	• At least one clinical and one laboratory criteria are needed for diagnosis of antiphospholipid syndrome.
	• The clinical criteria include arterial or venous thrombosis or obstetrical complications.
	• 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.

At least one clinical and one laboratory criterion should be met for diagnosing antiphospholipid syndrome (82; 50).

Clinical criteria

Vascular thrombosis. Clinical evidence of arterial, venous, or small-vessel thrombosis in vascular beds of any tissue or organ should be confirmed by diagnostic imaging or histopathology. 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 (12; 56).

These include the following:

	• Recurrent fetal loss (≥3) before 10 weeks of pregnancy in the absence of 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 due to uteroplacental insufficiency.

Laboratory criteria

The diagnostic criterion requires two or more abnormal laboratory values measured at least 12 weeks apart for the following antibodies:

	• Lupus anticoagulant; a false positive result may be due to warfarin, heparin, and direct oral anticoagulants.
	• Anticardiolipin, IgG, or IgM present in moderate to high titer (> 40 GPL or MPL or > 99th percentile) by 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 or dilute Russell viper venom time (dRVVT) are normal, a lupus anticoagulant is ruled out. If they are prolonged, full correction after the patient’s plasma is mixed with normal plasma excludes lupus anticoagulant. If correction does not occur after the mixing study but requires the addition of a phospholipid, lupus anticoagulant is confirmed.

Risk stratification is based on the antiphospholipid profile. A high-risk profile is characterized by the detection of lupus anticoagulant on two or more occasions at least 12 weeks apart, 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 transient (104).

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Adrian Marchidann MD

Dr. Marchidann of Kings County Hospital has no relevant financial relationships to disclose.
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Editor

Steven R Levine MD

Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
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Former Authors

Thomas L Ortel MD PhD
Jamil Y Abuzetun MD
Ribhi Hazin MD
Faisal Khan MD
Ambooj Tiwari MD
Khalid Shahram MD
Sharon S Cooperman MD
Kumar Rajamani MD
Yongwoo Kim MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: female>male, 1:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Other specified coagulation defects: D68.8
ICD-11: Antiphospholipid syndrome: 4A45

Coagulation defects, unspecified: 3B4Z
OMIM: Antiphospholipid syndrome: 107320

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Antiphospholipid antibody syndrome

Associated Disorders

Coronary artery disease
Deep venous thrombosis
Systemic lupus erythematous
Thrombophilias

Differential Diagnosis

multiple sclerosis
systemic lupus erythematous
human immunodeficiency virus
hemolytic anemia
systemic sclerosis
- Behçet syndrome
- hepatitis C
- Sneddon syndrome
- avascular necrosis
- vasculitis
- Cogan syndrome with hearing loss
- Susac syndrome with branch retinal artery occlusion

	• Acute thrombosis is treated with thrombolytics.
	• Association of antiphospholipid syndrome 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 high-risk patients (triple antibodies).
	• Rivaroxaban may be used if warfarin treatment is not practical but is less effective in high-risk patients.

Antiphospholipid antibody syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Anticoagulant downregulation.

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Clinical criteria

Laboratory criteria

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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