creation date: 2026-08-30 18:03
tags: Pathologies
Antiphospholipid Syndrome
Background
Definitions
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder. It is characterized by recurrent thrombosis and obstetric morbidity.
Catastrophic APS (CAPS) refers to a life threatening variant of APS characterized by rapid onset of symptoms, multi-organ involvement, and large and microvascular thrombotic events.
APS is a primary disease in 50% of the time. In the other 50%, patients have a concomitant systemic autoimmune disease, whereby systemic lupus erythematosus is the most common.
Pathogenesis
APS, being autoimmune in nature, involves antiphospholipid antibodies (aPL). The effect of this is:
- Lupus anticoagulant effect - the property of a group of antibodies which interfere with clotting; most associated with anti-beta2GPI and anti-prothrombin
- Anticardiolipin antibodies which leads to false-positive syphilis tests
Thrombotic antiphospholipid syndrome
aPL results in the activation of vascular and immune cells which upregulate surface adhesion molecules and release of proinflammatory cytokines and procoagulant substances.
Endothelial cells, monocytes, neutrophils, and platelets are activated which result in:
- Downregulation of vasoprotective processes
- Proinflammation
- Prothrombotic neutrophil extracellular traps
- Thombocytopenia
Additionally, aPL interfere with natural anticoagulant proteins (including protein S and C) as well as the fibrinolytic system. This potentiates the patient for thrombosis but does not necessarily trigger it.
A second hit, typically in the form of vascular injury, triggers acute thrombotic events.
Obstetric antiphospholipid syndrome
While intervillous thrombosis was thought to be the primary driver of pregnancy morbidity with APS, this is not reliably the case. Observations have suggested complications are mediated by trophoblast dysfunction and complement activation.
First trimester losses are attributed to direct inhibitory effects of aPL on trophoblast viability, proliferation, and invasion. Late-term loss are attributed to trophoblast dysfunction causing an insufficient placenta and direct inflammatory effects causing fetal growth restriction, preeclampsia, preterm birth, and fetal demise.
Risk Factors
Further risk factors increase thrombotic risk in patients with aPL:
- SLE
- Inherited thrombophilia
- Cancer
- Smoking
- Pregnancy
- Use of estrogen-containing oral contraceptives
- Immobilization
- Obesity
- Hypertension
- Hypercholesterolemia
Clinical Presentation
Signs & Symptoms
The hallmark features of APS include:
- Venous thrombosis
- Arterial thrombosis
- Small-vessel disease
- Specific pregnancy complications
- Livedo reticularis/racemosa
- Thrombocytopenia
- Autoimmun hemolytic anemia
- Cardiac valve disease
Associated conditions, in order of incidence, include:
- Deep vein thrombosis
- Thrombocytopenia
- Livedo reticularis
- Stroke
- Superficial thrombophlebitis
- Pulmonary embolism
- Fetal loss
- Transient ischemic attack
History & Physical Exam
History should include:
- Nature and frequency of thrombotic events
- Outcome of pregnancies
- Thrombocytopenia
- Other risk factors for thrombosis
- Risk factors for other thrombotic syndromes
- Use of anticoagulants
- Symptoms associated with SLE (arthritis/arthralgias, photosensitivity, oral ulcers, patchy hair loss, Raynaud phenomenon)
Physical exam should include:
- Skin (for livedo reticularis/racemosa)
- Cardiovascular (murmur, digital ischemia/gangrene)
- Neurologic (for signs of prior stroke)
- Extremities (for DVT sequelae)
Diagnosis
Criteria
APS is a clinical diagnosis made based on:
- Presence of at least one clinical manifestation (venous thrombosis, arterial thrombosis, pregnancy morbidity)
- Setting of persistently positive antiphospholipid antibodies (aPL) (positive on two separate occasions at least 12 weeks apart)
Clinical judgement is required to:
- Determine the correlation between clinical event and aPL
- Assess risk factors associated with clinical event
- Assess aPL profile
The diagnosis of APS is weakened when there are better explanation for clinical events.
Work-up
Laboratory evaluation
Routine lab testing include:
- CBC
- Coagulation studies
- Serum creatinine and urinalysis with urine sediment
Patients with features suggestive of SLE should receive testing for such.
Antiphospholipid antibody testing
ANtibody testing requires two immunoassays and a functional coagulation assay:
- Anticariolipin antibodies
- Anti-beta2 glycoprotein I antibodies
- LA testing
Testing is done shortly after a clinical event and a confirmatory test made at least 12 weeks later.
Antibody testing for other antibodies (eg. prothrombin) is not routine.
Differential
Other causes of thrombosis include:
- Inherited and acquired thrombophilia
- Anatomic vascular obstruction
- Paroxysmal nocturnal hemoglobinuria
- Heparin-induced thrombocytopenia
- Myeloproliferative neoplasms
Other causes of pregnancy morbidity are described with separately.
Antiphospholipid antibodies may be positive without antiphospholipid syndrome:
- Transient antiphsopholipid antibodies
- Persistent lupus anticoagulant or medium/high-titer aCL/aBGP1
- Autoimmune and rheumatic diseases
- Infections
- Medications (phenothiazines, phenytoin, hydralazine, procainamide, quinidine, amoxicillin, OCPs, and more)
- Malignancy
Red Flags / Complications
Complications may include:
- Pulmonary hypertension
- Cognitive dysfunction
- Brain white matter lesions
Management
Primary Thrombosis Prevention
Primary prevention is used for patients with obstetric APS or isolated aPL who have not yet had an APS-related thrombosis.
There is limited evidence for the benefit of use of antithrombotic (aspirin or anticoagulation) for patients with aPL without APS. However, it may be reasonable to choose to take aspirin, especially if they may derive other benefits or if they can tolerate the slightly elevated risk of bleeding.
Acute Thrombosis
In individuals presenting with a thrombotic event who has not had prior testing for aPL, a diagnosis cannot be made and can only be suspected (confirmation requires at least 12 weeks).
For patients suspected of APS, warfarin is preferred over a DOAC. This treatment typically lasts 3-6 months.
Secondary Thrombosis Prevention
Following the initial phase of acute thrombotic event treatment and confirmatory aPL testing, long term secondary prevention is indicated.
For most nonpregnant individuals, warfarin is recommended. INR targets are 2-3. For arterial thrombosis cases, addition of a low-dose aspirin or increasing warfarin intensity (>3) may be considered.
Anticoagulation is recommended lifelong.