What diseases are associated with antiphospholipid antibodies (aPL)?

Diseases Associated with Antiphospholipid Antibodies

Antiphospholipid antibodies (aPL) are associated with a spectrum of thrombotic and autoimmune conditions, most notably antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), and various other rheumatologic, hematologic, infectious, and malignant diseases. 1

Primary Disease Association: Antiphospholipid Syndrome

The defining disease associated with aPL is antiphospholipid syndrome (APS), characterized by venous and arterial thrombosis, recurrent pregnancy loss, and thrombocytopenia. 1, 2 APS requires both persistent laboratory positivity (confirmed on repeat testing at least 12 weeks apart) AND clinical manifestations to establish the diagnosis. 3, 4

Clinical Manifestations of APS:

• Venous thromboembolism: Deep vein thrombosis and pulmonary embolism are the most common thrombotic events 1, 5
• Arterial thrombosis: Stroke, transient ischemic attack, coronary artery thrombosis, and peripheral arterial occlusion 1, 5
• Cerebrovascular disease: Particularly in young adults (<50 years), with 9.7% of ischemic stroke patients demonstrating anticardiolipin antibodies 1
• Obstetric complications: Recurrent fetal loss (typically second- or third-trimester miscarriages), late pregnancy loss, and other pregnancy morbidities 1, 6, 2
• Thrombocytopenia: Often mild to moderate 2, 7
• Cardiac valve disease: Valve alterations and vegetations 1
• Catastrophic APS (CAPS): Multi-organ thrombosis requiring triple therapy with anticoagulation, high-dose glucocorticoids, and plasma exchange 4

Autoimmune and Rheumatologic Diseases

Systemic lupus erythematosus (SLE) is the most common autoimmune disease associated with aPL, with approximately 30% of SLE patients harboring antiphospholipid antibodies. 4, 8 This represents secondary APS, which carries worse outcomes compared to primary APS. 4

Other Rheumatologic Associations:

• Systemic sclerosis 8
• Sjögren's syndrome 8
• Rheumatoid arthritis 8
• Behçet's disease 8

Hematologic Disorders

Several hematologic conditions are associated with aPL and can present with neurologic manifestations including stroke:

• Hemolytic-uremic syndrome: Presents with seizures, hemiparesis, aphasia, and visual field defects from ischemic or hemorrhagic infarction 1
• Thrombotic thrombocytopenic purpura (TTP): Distinguished by severely reduced ADAMTS13 activity (≤10%), with fever, microangiopathic hemolytic anemia, renal dysfunction, and fluctuating neurological signs 1, 4
• Paroxysmal nocturnal hemoglobinuria: Can lead to cerebral venous and arterial thromboses 1
• Polycythemia rubra vera and essential thrombocythemia: May cause cerebral infarction or intracranial hemorrhage 1
• Disseminated intravascular coagulation 1
• Heparin-induced thrombocytopenia 1

Malignancies

aPL are detected in patients with cancer, with specific types of aPL considered markers of oncological progression. 8, 9 Cancer-related thrombosis is recognized as an acquired hypercoagulable state associated with aPL positivity. 1

Infectious Diseases

Infections can trigger transient aPL positivity, distinguishing them from the persistent antibodies required for APS diagnosis. 8, 9 This includes various viral, bacterial, and parasitic infections, with COVID-19 emerging as a notable risk factor for aPL development. 9

Neurologic Disorders

Beyond stroke, aPL are detected in patients with various neurological disorders:

• Cerebral venous thrombosis: Particularly in children with prothrombotic states 1
• Retinal vessel thrombosis 5
• Livedo reticularis 1

Asymptomatic Carriers

Healthy individuals may be asymptomatic carriers of aPL (Type VI patients), with chronic asymptomatic aPL presence most common in the elderly and subjects with chronic diseases. 8, 5 aPL occur in 6% of pregnant women without diagnosed APS and are related to pregnancy complications. 8

Prevalence Considerations:

• General population prevalence ranges from 1% to 6.5% 1
• Higher prevalence in elderly populations 1
• Low-titer antibodies may not confer the same thrombotic risk as moderate-to-high titers 6

Risk Stratification by Antibody Profile

Triple positivity (lupus anticoagulant + anticardiolipin + anti-β2-glycoprotein I) carries the highest thrombotic risk, with a relative risk of 12.15 for adverse pregnancy outcomes. 3, 4 IgG isotype antibodies show stronger association with clinical events than IgM antibodies, particularly in thrombotic APS. 3, 4