Diagnosis of Antiphospholipid Syndrome: A Comprehensive Guide for Auto Repair Experts

Introduction

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies (APLAs). These autoantibodies target phospholipid-binding proteins, leading to a predisposition for thrombosis and pregnancy complications. The diagnosis of APS is crucial for effective management and prevention of severe health outcomes. This condition is marked by the occurrence of arterial or venous thrombosis, or pregnancy morbidity, in individuals who consistently test positive for APLAs. While thrombosis can manifest in various organs, the lower limbs and cerebral arterial circulation are the most commonly affected sites for venous and arterial events, respectively. Catastrophic antiphospholipid syndrome (CAPS), a rare but life-threatening complication, necessitates prompt diagnosis and aggressive treatment due to its high mortality rate. Accurate diagnosis of APS relies on a combination of clinical criteria and laboratory findings, requiring a thorough evaluation and a collaborative approach from an interprofessional healthcare team. This article provides a detailed overview of the diagnostic process for APS, aiming to enhance the understanding and management of this complex syndrome.

Etiology of Antiphospholipid Syndrome

Antiphospholipid syndrome can be categorized as primary or secondary. Primary APS occurs independently, without association with other autoimmune diseases. Secondary APS, conversely, develops in conjunction with autoimmune conditions, most notably systemic lupus erythematosus (SLE), which accounts for approximately 40% of secondary APS cases. Studies have indicated a notable prevalence of APLAs in certain populations, including pregnant women (6%), stroke patients (13.5%), and individuals with deep venous thrombosis (DVTs) (9.5%).

Genetic predispositions also play a role in the etiology of APS. Specific HLA alleles, such as HLA-DR7, DR4, DRw53, DQw7, and C4 null alleles, have been linked to an increased risk of developing APS. Furthermore, infections, particularly viral infections, have been implicated in triggering elevated APLA levels. Pathogens such as Borrelia burgdorferi, Coxiella burnetii, Treponema pallidum, hepatitis C virus, HIV, COVID-19, Epstein-Barr virus (EBV), and Leptospira species have all been associated with APLA formation. Notably, a meta-analysis of COVID-19 patients revealed that nearly half tested positive for APS, predominantly for lupus anticoagulant, although no increased thrombotic risk was observed in these APLA-positive COVID-19 patients.

Certain medications, including chlorpromazine, procainamide, quinidine, and phenytoin, are also known to induce APLA production. The diagnosis of APS requires persistence of APLAs, as transient, low levels can occur normally. Therefore, positive antibody tests must be confirmed at least 12 weeks apart to establish a diagnosis of APS.

Clinically, APS can be further classified based on its manifestations. Obstetric APS is diagnosed based on pregnancy-related complications, such as premature birth due to preeclampsia, fetal death after 10 weeks of gestation, placental insufficiency, or recurrent embryonic losses before 10 weeks, coupled with persistent APLA laboratory criteria. Patients exhibiting both thromboembolic events and obstetric complications are classified as having both thrombotic and obstetric APS.

Epidemiology of Antiphospholipid Syndrome

The epidemiological landscape of APS varies geographically. In the United States, the estimated incidence is approximately 2.1 cases per 100,000 individuals, with a prevalence of 50 per 100,000. European rates are generally lower, with an incidence around 1.1 per 100,000. Asian countries also report lower rates; for instance, South Korea has an incidence of 0.75 per 100,000 and a prevalence of 6.19 per 100,000.

Low-titer anticardiolipin antibodies can be detected in up to 10% of healthy individuals, and the likelihood of a positive APLA test increases with age. A study on centenarians without autoimmune disease showed that 54% tested positive for anti-β2GPI-IgG and 21% for anticardiolipin-IgG. Interestingly, none were positive for lupus anticoagulant, suggesting it may be a more specific marker for APS. However, high titers and persistent positivity of APLAs are uncommon in healthy individuals, occurring in less than 1%.

Patients with SLE face a significantly elevated risk of APLA positivity and subsequent APS-related clinical outcomes like thrombosis or pregnancy morbidity. It is estimated that 50% to 70% of SLE patients with positive APLAs will progress to develop APS.

APLA positivity is also observed in up to 20% of patients with rheumatoid arthritis. Studies involving couples with recurrent abortions have found APLA positivity in around 20% of cases. Furthermore, APLAs, such as lupus anticoagulant or anticardiolipin antibodies, have been detected in 14% of patients with recurrent venous thromboembolism.

Pathophysiology of Antiphospholipid Syndrome

While the mere presence of APLAs does not guarantee the development of APS, a strong correlation exists between APLAs and thrombotic events, including venous thrombosis, myocardial infarction, and ischemic stroke. The specific antibody profile, encompassing antibody type, titer, and underlying comorbidities, significantly influences the risk of developing clinical APS. Triple positivity, defined by positive lupus anticoagulant and high titers of anticardiolipin and anti-β2GPI antibodies, indicates a particularly high risk. Conversely, isolated or intermittent positivity or low titers of anticardiolipin or anti-β2GPI antibodies are associated with a lower risk.

Patients with SLE, pre-existing cardiovascular risk factors, a history of recurrent thrombotic events despite anticoagulation, and arterial thrombosis are also at heightened risk of recurrent thrombosis. APLAs are not merely serological markers; they are considered pathogenic, actively contributing to thrombosis in APS (See Image. Antiphospholipid Syndrome).

Alt text: Illustration depicting the relationship between antiphospholipid antibodies (APLAs) and antiphospholipid syndrome (APS), highlighting abnormal blood clot formation.

The “two-hit” thrombosis model is proposed to explain thrombus formation in APS. The first “hit” involves endothelial injury, while the second “hit” amplifies thrombus formation. Beta-2-glycoprotein-I, a key protein in APS, does not typically bind to unstimulated endothelium in vivo. It is hypothesized that endothelial injury, potentially due to redox imbalance within vascular beds, primes the endothelium. Patients with APS often have reduced levels of the reduced, protective beta-2 glycoprotein-I. Annexin A2, an endothelial cell surface receptor, becomes upregulated under oxidative stress. Factors like smoking can further induce endothelial injury and increase pro-thrombotic susceptibility in individuals with lupus anticoagulants.

Plasma nitrite levels are found to be decreased in APS patients compared to healthy individuals. Reduced expression and activity of endothelial nitric oxide synthase lead to the generation of peroxynitrite and superoxide. Preclinical studies have shown that domain I of beta-2 glycoprotein-I autoantibodies can inhibit endothelial nitric oxide synthase activity, resulting in monocyte adhesion and impaired nitric oxide-dependent arterial relaxation.

APLAs promote tissue factor expression through intracellular signaling pathways after binding to anti-β2GPI autoantibodies on monocytes and endothelial cells. Autoantibodies in APS disrupt neutrophil and monocyte mitochondrial function, increasing reactive oxygen species production and subsequent tissue factor expression. Complement activation and fibrinolysis inhibition by APLAs are also established components of the pathophysiology.

In APS-associated pregnancy loss, intraplacental thrombosis, complement pathway activation, interference with trophoblast growth and differentiation, impaired trophoblastic invasion, and hormonal effects are implicated. A study of pregnant women with fetal loss after 20 weeks found that 9.6% were positive for at least one APLA.

Histopathology of Antiphospholipid Syndrome

Renal biopsies from APS patients with kidney involvement typically reveal thrombotic microangiopathy. Characteristic findings include fibrin thrombi in glomeruli or arterioles without significant inflammation or immune complexes, fibrous intimal hyperplasia, and focal cortical atrophy. Thyroidization may also be present, and these lesions should be differentiated from lupus nephritis lesions.

Skin biopsies from non-healing ulcers are usually non-specific and not routinely performed but might show small vessel and endothelial proliferation without notable vasculitis. Cardiac biopsies, if performed, could show small vessel thrombosis. Bronchoalveolar lavage may reveal hemosiderin-laden macrophages, and lung biopsies might demonstrate capillaritis or microthrombi.

History and Physical Examination for Diagnosis of Antiphospholipid Syndrome

Clinical presentations of APS are highly variable, ranging from asymptomatic APLA positivity to severe CAPS. Vascular thrombosis, both arterial and venous, and pregnancy-related complications are the primary hallmarks of APS. However, non-criteria manifestations involving other organ systems can also occur. A detailed history and physical examination are crucial steps in the diagnosis of antiphospholipid syndrome.

Vascular Thrombosis

APS can cause arterial or venous thrombosis in any organ system. These thrombotic events can be isolated or recurrent and may involve unusual sites for thrombosis, such as upper extremity thrombosis, Budd-Chiari syndrome, and sagittal sinus thrombosis. DVTs are the most frequent venous manifestation and can lead to pulmonary embolism and pulmonary hypertension. Other venous sites affected may include pelvic, renal, mesenteric, hepatic, portal, axillary, ocular, sagittal, and inferior vena cava.

Arterial thrombosis in APS can affect arteries of any size, from the aorta to small capillaries. Transient ischemic events (TIAs) and ischemic stroke are the most common arterial manifestations. APS should be suspected in young patients experiencing TIAs or ischemic stroke without traditional atherosclerosis risk factors. Other arterial sites of thrombosis include retinal, brachial, coronary, mesenteric, and peripheral arteries. Arterial thrombosis carries a poorer prognosis due to the high risk of recurrence.

Pregnancy Morbidity

Pregnancy loss is a significant complication in APS, particularly in the second or third trimester. While genetic and chromosomal abnormalities are more common causes of early pregnancy loss, fetal loss after 20 weeks is associated with approximately 10% APLA positivity. Triple positivity for lupus anticoagulant, anticardiolipin, and anti-β2GPI antibodies, along with a history of prior pregnancy loss, thrombosis, and SLE, are risk factors for adverse pregnancy outcomes and pregnancy losses in APS patients. Additional pregnancy-related complications include preeclampsia, fetal distress, premature birth, intrauterine growth retardation, placental insufficiency, placental abruption, and HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count).

Cutaneous Involvement

Various cutaneous manifestations have been reported in APS, though none are specific. Livedo reticularis is the most common, but it can also occur in healthy individuals and other conditions like SLE, connective tissue diseases, vasculitides, sepsis, cholesterol emboli, and Sneddon syndrome. Skin ulcerations, particularly in the lower extremities, ranging from small to pyoderma gangrenosum-like ulcers, have been observed. Other cutaneous signs include nail-fold infarcts, digital gangrene, superficial thrombophlebitis, and necrotizing purpura.

Valvular Involvement

Cardiac valve involvement is frequent in APS, with some studies reporting prevalence as high as 80%. Mitral and aortic valves are most commonly affected, showing thickening, nodules, and vegetations on echocardiography, potentially leading to regurgitation or stenosis.

Hematological Involvement

Thrombocytopenia is seen in over 15% of APS cases. Severe thrombocytopenia with hemorrhage is rare. A positive Coombs test is frequently observed, although hemolytic anemia is less common.

Neurological Involvement

The most common neurological complications are TIAs and ischemic stroke, which can be recurrent, leading to cognitive dysfunction, seizures, and multi-infarct dementia. Blindness can result from retinal artery or vein occlusion, and sudden deafness due to sensorineural hearing loss has also been reported.

Cardiac Involvement

Myocardial infarction and cardiac emboli are potential cardiac complications of APS. Non-ST segment elevation myocardial infarction with normal coronary angiogram but abnormal cardiac MRI findings, such as transmural or subendocardial late gadolinium enhancement, T2 abnormalities, or perfusion defects, may suggest APS.

Pulmonary Involvement

Pulmonary artery thromboembolism from DVT is common and can lead to pulmonary hypertension. Diffuse pulmonary hemorrhage due to pulmonary capillaritis has also been reported.

Renal Involvement

Hypertension, proteinuria, and renal failure secondary to thrombotic microangiopathy are classic but non-specific renal manifestations of APS. Renal artery thrombosis leading to refractory hypertension and focal cortical atrophy are other reported renal complications.

Catastrophic Antiphospholipid Syndrome (CAPS)

CAPS is a rare, life-threatening complication of APS, affecting less than 1% of APS patients. Mortality is high (48%), particularly in patients with SLE or cardiac, pulmonary, renal, and splenic involvement. CAPS is characterized by rapid, multi-organ thrombosis over days, commonly involving small- and medium-sized arteries. Clinical presentation varies by organ involvement and can include peripheral thrombosis, pulmonary complications (ARDS, pulmonary embolism, hemorrhage), renal manifestations (thrombotic microangiopathy, renal failure), cutaneous symptoms (livedo reticularis, digital ischemia, gangrene, ulcers), cerebral manifestations (ischemic stroke, encephalopathy), cardiac complications (valve lesions, myocardial infarction, heart failure), hematological issues (thrombocytopenia), and gastrointestinal involvement (bowel infarction).

Common triggers for CAPS are stopping anticoagulation in APS patients, infections, and surgical procedures. Prompt infection management and minimizing perioperative anticoagulation interruption are crucial.

Preliminary classification criteria for CAPS, published in 2003, include:

• Involvement of 3 or more organs, systems, or tissues.
• Manifestations developing simultaneously or within less than 1 week.
• Histopathological confirmation of small vessel occlusion in at least one organ or tissue.
• Laboratory confirmation of APLA presence.

All four criteria indicate definite CAPS, while probable CAPS is diagnosed if three criteria are fully met and the fourth is partially fulfilled.

Evaluation and Diagnosis of Antiphospholipid Syndrome

Diagnosis of antiphospholipid syndrome requires fulfillment of both clinical and laboratory criteria. Laboratory criteria include the presence of lupus anticoagulant or moderate-to-high titers of IgG or IgM anticardiolipin or anti-β2GPI antibodies. Crucially, a repeat APLA test must be positive at least 12 weeks after the initial positive test to rule out transient antibodies. A diagnosis of APS becomes questionable if the interval is less than 12 weeks or if the gap between clinical manifestations and positive laboratory tests exceeds 5 years. For detailed information, refer to StatPearls’ resource, “Antiphospholipid Antibody Testing.”

Lupus Anticoagulant Test

A positive lupus anticoagulant test is a strong predictor of adverse pregnancy outcomes. This test is more specific but less sensitive than anticardiolipin antibody tests for predicting thrombosis. A positive lupus anticoagulant test is found in approximately 20% of patients with anticardiolipin antibodies, while anticardiolipin antibodies are found in 80% of those with a positive lupus anticoagulant test (See Table. Effect of Lupus Anticoagulant and Anticoagulants on Laboratory Testing).

Alt text: Table illustrating the impact of lupus anticoagulant and various anticoagulants like warfarin and dabigatran on clotting and anticoagulation laboratory tests.

A false-positive syphilis test alone does not meet APS diagnostic criteria, but APLA assessment is advised in patients with prior thrombotic or adverse pregnancy events. Lupus anticoagulant indicates an in vitro coagulation inhibitor of phospholipid-dependent reactions. This inhibitor does not directly interact with coagulation factors and is not associated with bleeding complications. False-positive and false-negative results can occur in patients on heparin or warfarin.

The lupus anticoagulant test involves four steps:

1. Initial Screening: Typically using activated partial thromboplastin time (aPTT) or dilute Russell viper venom time (dRVVT), showing prolonged phospholipid-dependent clot formation.
2. Mixing Studies: The prolonged screening test remains prolonged even after mixing patient plasma with normal platelet-poor plasma, indicating the prolongation is not due to factor deficiencies.
3. Phospholipid Correction: The prolonged screening test is corrected or improved by adding excess phospholipid, confirming phospholipid dependency.
4. Inhibitor Exclusion: Ruling out other inhibitors.

Anticardiolipin and Anti-Beta-2-Glycoprotein-I Antibodies

Anticardiolipin and anti-β2GPI antibodies are measured by ELISA, typically assessing IgG and IgM isotypes. IgG antibodies show better correlation with clinical manifestations than IgM or IgA. Titers above 40 IgG units are associated with thrombotic events, while lower titers have a less established link.

Other Laboratory Findings

Thrombocytopenia or anemia may be present in APS. Renal failure and proteinuria can indicate renal involvement with thrombotic microangiopathy. Erythrocyte sedimentation rate may be elevated during acute thrombosis but is usually normal otherwise. SLE-specific serologies, such as antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), or anti-Smith (anti-Sm) antibodies, may be positive in patients with secondary APS. Hypocomplementemia is not typical in APS and, if present with renal involvement, may suggest lupus nephritis.

Importantly, positive ANA and anti-dsDNA antibodies can be observed in primary APS without SLE, and their presence alone does not diagnose SLE in the absence of clinical lupus features. Patients with recurrent thrombosis or pregnancy losses should also be evaluated for other hypercoagulable states, such as hyperhomocysteinemia, factor V Leiden and prothrombin mutations, or deficiencies of protein C, protein S, or antithrombin III, as indicated.

Classification Criteria for Diagnosis of Antiphospholipid Syndrome

The initial Sapporo criteria for APS classification were published in 1999 and revised in 2006. The revised Sapporo criteria require at least one clinical and one laboratory criterion for APS diagnosis.

Clinical Criteria

At least one of the following clinical findings must be present:

Vascular Thrombosis:

• One or more objectively confirmed events of arterial, venous, or small-vessel thrombosis in any organ. Confirmation requires appropriate imaging or histopathology, with thrombosis typically present without significant vessel wall inflammation.
  • Past thrombotic episodes are acceptable if appropriately confirmed and no other cause for thrombosis is identified.
  • Superficial venous thrombosis is not considered a criterion.

Pregnancy Morbidity:

• One or more unexplained fetal deaths of morphologically normal fetuses at or beyond 10 weeks of gestation, confirmed by ultrasound or direct examination.
• One or more premature births of morphologically normal neonates before the 34th week of gestation due to eclampsia, severe preeclampsia, or placental insufficiency.
• Three or more consecutive spontaneous abortions before the 10th week of gestation, after excluding maternal anatomical or hormonal abnormalities and parental chromosomal causes.

Laboratory Criteria

At least one of the following laboratory findings must be confirmed:

• Lupus anticoagulant detected in plasma on 2 or more occasions, at least 12 weeks apart.
• IgG or IgM anticardiolipin antibodies in serum or plasma at moderate-to-high titers (more than 40 GPL or GPM, or GPL/GPM >99th percentile) by standard ELISA on 2 or more occasions, at least 12 weeks apart.
• IgG or IgM anti-β2GPI antibodies in serum or plasma at moderate-to-high titers (>99th percentile) by standard ELISA on 2 or more occasions, at least 12 weeks apart.

The 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) APS classification criteria introduced a new approach. These criteria begin with an entry criterion of at least one positive APLA test within 3 years of an APS-associated clinical criterion. Following this, weighted criteria are applied, with scores ranging from 1 to 7 points across six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant tests and IgG/IgM anticardiolipin or IgG/IgM β2GP1). A classification of APS is given to patients scoring at least 3 points from both clinical and laboratory domains. Compared to the 2006 revised Sapporo criteria, the new ACR/EULAR criteria show increased specificity (99% vs. 86%) but decreased sensitivity (84% vs. 99%). The detailed criteria are available at DOI: 10.1002/art.42624.

Treatment and Management of Antiphospholipid Syndrome

Thrombosis Management

EULAR guidelines provide specific recommendations for various clinical scenarios in APS management. Primary thromboprophylaxis in APLA-positive patients without prior thrombosis or pregnancy complications is debated. Confirmatory APLA testing is necessary at least 12 weeks post-initial testing. SLE patients with positive APLAs are at higher thrombotic risk, and hydroxychloroquine is recommended for its thromboprotective effects. Low-dose aspirin may also be considered. Prophylaxis with low-dose aspirin may be considered for other APLA patients with high-risk profiles, such as triple positivity and additional thrombotic risk factors, but no history of thrombosis.

Primary Prevention: High-risk patients include those with positive lupus anticoagulant, 2 or 3 positive APLAs, or persistently high APLA levels.

• For high-risk APLA profile patients without prior thrombotic events, low-dose aspirin (75-100 mg) is recommended.
• In SLE patients without thrombosis or pregnancy complications:
  • With a high-risk APLA profile, low-dose aspirin prophylaxis is recommended.
  • With a low-risk APLA profile, low-dose aspirin prophylaxis may be considered.
  • In nonpregnant women with obstetric APS history only (with or without SLE), low-dose aspirin prophylaxis is recommended after risk/benefit assessment.

Secondary Prevention

• Arterial Thrombosis: Warfarin is generally preferred over direct oral anticoagulants (DOACs) for arterial thrombosis. The target INR range is debated, with 2.0 to 3.0 being common, though some suggest >3.0.

  • Low-molecular-weight heparin (LMWH) is an option for warfarin-intolerant or unresponsive patients.
  • For recurrent thrombosis despite adequate warfarin, adding aspirin, switching to LMWH, or increasing INR target to >3.0 can be considered. Warfarin adherence and INR monitoring should be assessed.
  • DOACs may be considered for warfarin contraindications or INR management issues. Dabigatran may be more effective than other DOACs due to its anti-factor IIa mechanism.
  • Low-dose aspirin can be used for elderly stroke patients with low-titer anticardiolipin antibodies, as these antibodies may be incidental.

• Lupus anticoagulant can falsely prolong aPTT, PT, and INR. Prothrombin levels or factor X activity measurement can mitigate this, though not universally available (See Table. Effect of Lupus Anticoagulant and Anticoagulants on Laboratory Testing).

Triple Positivity: Recent trials comparing rivaroxaban and apixaban to warfarin showed DOACs to be inferior, with some trials terminated early due to excess thrombosis in DOAC groups. Therefore, warfarin is recommended over DOACs for APS patients with triple positivity (lupus anticoagulant, anticardiolipin, and anti-β2GP1 positive) or arterial thrombosis and APS. Some guidelines suggest warfarin over DOACs for any APS patient with a thrombotic event, venous or arterial.

Pregnancy Management

Pregnant women with positive APLAs require close monitoring for fetal well-being and maternal complications. Treatment aims to reduce adverse fetal outcomes and depends on the clinical scenario. Warfarin is teratogenic and contraindicated in pregnancy. DOACs are also avoided due to safety data scarcity, though not definitively teratogenic. LMWH is preferred over unfractionated heparin due to better bioavailability, longer half-life, convenient dosing, and lower risks of thrombocytopenia and osteoporosis. EULAR recommendations for pregnant women include:

• Positive APLA, no thrombosis history:

  • First pregnancy: No treatment indicated.
  • Single pregnancy loss <10 weeks gestation: No treatment indicated.
  • High-risk APLA profile, no thrombosis/pregnancy complications: Low-dose aspirin may be considered.

• History of delivery <34 weeks gestation due to eclampsia, preeclampsia, or placental insufficiency: Low-dose aspirin or low-dose aspirin plus prophylactic heparin based on risk profile.

• History of less defined criteria (2 miscarriages <10 weeks, or delivery >34 weeks due to eclampsia/preeclampsia): Low-dose aspirin or prophylactic heparin based on risk profile.

• Definite obstetric APS with recurrent pregnancy complications despite low-dose aspirin and prophylactic heparin/LMWH: Increasing heparin to therapeutic dose or adding hydroxychloroquine or low-dose prednisolone in the first trimester may be considered. IVIG might be considered in select cases when other treatments fail.

• History of thrombotic APS: Combination of low-dose aspirin and therapeutic dose heparin during pregnancy is recommended. Observational studies show approximately 79% live birth rate with this regimen. Switch from warfarin to therapeutic heparin/LMWH upon pregnancy confirmation, ideally before 6th week, due to warfarin teratogenicity.

Management of Other Manifestations

Anticoagulation role is unclear for non-criteria APS manifestations. Thrombocytopenia with platelet count >50,000/mL3 generally requires no treatment; corticosteroids with or without IVIG or rituximab can be used for platelet counts <50,000/mL3. Splenectomy has benefited some with refractory thrombocytopenia.

Renal involvement with thrombotic microangiopathy requires renal biopsy to exclude lupus nephritis, especially in SLE patients. Anticoagulation and corticosteroids can be used for thrombotic microangiopathy. Effective treatment for cardiac valve nodules/deformities is unknown, but anticoagulation is recommended if embolism or intracardiac thrombus is present.

Catastrophic Antiphospholipid Syndrome (CAPS) Management

Early CAPS diagnosis is critical due to high mortality. Combination therapy with glucocorticoids, heparin, and plasma exchange or IVIG is recommended as first-line treatment over single agents. Concurrent treatment of precipitating factors like infections, gangrene, or malignancy is also crucial. Refractory CAPS may warrant B-cell depletion (rituximab, cyclophosphamide) or complement inhibition (eculizumab), based on case report data.

Follow-up Monitoring

Stable anticoagulated patients without systemic autoimmune diseases can have outpatient visits 1-2 times yearly. Coagulation studies are done pre- and during anticoagulation for dosing. Biochemistry panels (renal function tests) and complete blood counts are used for monitoring. Repeat APLA testing is not typically indicated unless needed for future treatment decisions. Symptomatic organ involvement necessitates appropriate evaluations based on symptoms.

Differential Diagnosis of Antiphospholipid Syndrome

Thrombosis due to APS must be differentiated from other thrombophilic conditions such as hyperhomocysteinemia, factor V Leiden and prothrombin mutations, or deficiencies of protein C, protein S, or antithrombin III.

APS-associated nephropathy must be distinguished from thrombotic thrombocytopenic purpura (TTP), vasculitis, hemolytic uremic syndrome, malignant hypertension, and lupus nephritis. Kidney biopsy is often necessary for definitive diagnosis in these cases.

Prognosis of Antiphospholipid Syndrome

European studies report 10-year survival rates of 90% to 94% in APS. However, morbidity is significant, with over 30% developing permanent organ damage and over 20% severe disability at 10-year follow-up. Poor prognostic factors include CAPS, pulmonary hypertension, nephropathy, CNS involvement, and extremity gangrene.

Prognosis is similar for primary and secondary APS, but secondary APS may have increased morbidity due to underlying rheumatic or autoimmune disorders. Lupus patients with APLAs have higher neuropsychiatric disorder risk.

APLAs are often elevated in malignancy and are associated with poor prognosis, with or without thromboses.

Complications of Antiphospholipid Syndrome

APS complications relate to affected organs and include fetal loss, stroke, pulmonary embolism, pulmonary hypertension, valvular abnormalities, acute coronary syndrome, mesenteric thrombosis, or hepatic veno-occlusive disease.

Perioperative complications are common in APS due to increased surgical prothrombotic risk. Preoperative anticoagulation strategy must be defined to prevent thrombosis.

Consultations for Antiphospholipid Syndrome

APS patients often require consultation with internists, rheumatologists, hematologists, and obstetricians.

Deterrence and Patient Education for Antiphospholipid Syndrome

Patients should be educated about APS complications and symptoms requiring medical attention, such as TIA indicators. Clear communication about medication regimens and adherence is essential. Warfarin patients may require frequent INR monitoring and dietary guidance to avoid warfarin interference.

Pearls and Other Issues in Antiphospholipid Syndrome Management

Identifying and managing other prothrombotic risk factors like hyperlipidemia, smoking, hypertension, and oral contraceptive use is crucial in APS patients.

Enhancing Healthcare Team Outcomes in Antiphospholipid Syndrome

APS management requires an interprofessional team approach involving primary care physicians, hematologists, rheumatologists, pharmacists, specialty nurses, and potentially neurologists, nephrologists, cardiologists, and dermatologists depending on organ involvement. Obstetric and maternal-fetal medicine specialists are vital for pregnancy-related APS. Anticoagulation clinics are valuable for warfarin and INR monitoring. Effective communication and collaborative care are essential for optimal APS management and patient outcomes.

Review Questions

(Original review questions are retained in the online article)

References

(Original references are retained and linked in the online article)

Disclosures:

(Original disclosures are retained)