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BACKGROUND

Antiphospholipid syndrome (APS) is characterized by arterial, venous, or small vessel thromboembolic events and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). APS can be primary or secondary to an underlying rheumatic disease (usually SLE). Most common manifestations include DVT/PE, thrombocytopenia, livedo reticularis, stroke/TIA, fetal loss, and hemolytic anemia. Catastrophic APS (CAPS) is a severe form of APS manifesting as (near-)simultaneous micro/macro-vascular thrombosis in multiple organs with/without thrombotic microangiopathy and hemolysis. Investigations should include basic screening for anemia, thrombocytopenia, renal failure, baseline coagulation studies; lupus serology may be sent depending on clinical suspicion. aPL antibodies should be persistently positive for ≥12 weeks: lupus anticoagulant, anti-beta2 glycoprotein I, and anti-cardiolipin. Treatment of thrombosis in APS generally requires vitamin K antagonists life-long. Pregnant women with definite thromboic APS require low molecular weight heparin and low dose aspirin in pregnancy. CAPS requires steroids, heparin, and either PLEX or IVIG.
[🕑15 minute read]

EPIDEMIOLOGY

 Precise epidemiological data limited: few studies, inter-assay and inter-laboratory variation in anti-phospholipid (aPL) antibodies

• Prevalence of aPL-antibodies in General Population
  • Prevalence of aPL-antibodies in general healthy population: 1-5%
  • Prevalence of aPL-antibodies naturally increases with age, especially older patients with coexistent chronic diseases.
  • Persistence is important:
    • 10% of healthy blood donors test positive for anticardiolipin antibodies, but after 1 year, <1% remain positive, highlighting the importance of persistent positivity
• Prevalence of aPL-antibodies in Thrombosis Population
  • Stroke: ~13%;
  • Stroke in patients under <50 years-old: 17%
  • Myocardial infarction: ~11%
  • Deep Vein thrombosis: ~9.5%
  • Pregnancy complications: ~6% (IQR 2-13%).
• APS in General Population
  • Estimated incidence: ~2/100,000 annually.   
  • Estimated prevalence:  ~10-50/100,000
  • Age: Predominantly affects young adults, though disease can occur at any age
    • Mean age at diagnosis ~54 years in one population-based study
  • Sex: F>M
    • ~3.5:1 in primary APS
    • ~7:1 in SLE-associated APS
    • (population-based data suggest more equal sex distribution)
• Relationship between APS and SLE
  • SLE in the APS population
    • Prevalence of SLE in APS: 18-40% (varies by cohort)
    • Incidence of SARD in APS: 23% of APS patients developed systemic autoimmune disease over 9.75 year follow-up
    • aPL antibodies in the SLE population
      • Prevalence of aPL-antibodies in SLE:  30-40%
    • SLE phenotype:
      SLE patients with positive aPL antibodies have increased frequency of
      • Thrombosis
      • Thrombocytopenia
      • Hemolytic anemia
      • Hypocomplementemia
      • Microvascular disease
      • Pulmonary hypertension

CLINICAL MANIFESTATIONS

—Terminology

Thrombotic APS	Based on venous or arterial thrombosis and lab criteria for aPL
Obstetric APS	Based on APS-defining pregnancy morbidity (ex: fetal death >10 weeks, premature birth due to preeclampsia or placental insufficiency, or multiple losses < 10 weeks) and lab criteria for APL
CAPS	Rare life-threatening APS characterized by (near-)simultaneous thrombosis involving multiple organs, often with microvascular involvement

—Most common manifestations

• Deep vein thrombosis (32%)
• Thrombocytopenia (22-50%; prevalence varies by definition — mild vs. clinically significant thrombocytopenia)
• Livedo reticularis (20%)
• Stroke (13%)
• Superficial thrombophlebitis (9%)
• Pulmonary embolism (9%)
• Fetal loss (8%)
• TIA (7%)
• Hemolytic anemia (6%)
• Other
  • Migraine (frequent)
  • Cognitive dysfunction (frequent)

—Thrombotic events

• Recurrent thrombosis rate high if untreated: ~25%/year in one retrospective cohort; 29% over 4 years in another study
• Highest risk of thrombosis:
  • Persistent presence of LAC
  • Double positive aPL
    (any 2 of lupus anticoalgulant, anti-cardiolipin, anti-beta2 glycoprotein 1 [LAC, aCL, β2BPI])
  • Triple positive aPL
    Triple-positive patients had a 30% rate of thrombotic recurrence even while on anticoagulant therapy in some cohorts
• Presentation
  Venous more common than arterial thrombosis.
  • Most common venous thrombosis
    • Lower-limb DVT ±PE and chronic thromboembolic pulmonary hypertension
  • Most common arterial thrombosis
    • Stroke or TIA
  • Other presentations:
    • Acute coronary syndrome
    • Budd-Chiari syndrome (hepatic venous thrombosis)
    • Portal/mesenteric/splenic ischemia
    • Pancreatic or adrenal insufficiency

—Obstetrical APS

Prevalence of adverse pregnancy outcomes in women with APS despite treatment: 30% (triple-positive) to 80% (LAC-only)

• Pregnancy losses
  • Early pregnancy losses: ≥3 losses <10 weeks gestation
  • Later pregnancy losses: ≥1 Pregnancy loss ≥10 weeks
• Associated with placental ischemia
  • Intrauterine death
  • Pre-eclampsia/placental insufficiency
  • Premature birth
  • Intrauterine growth restriction: fetal weight below 10th percentile for gestational age
• Other features
  • Gestation-related maternal thrombosis
  • If hemolysis, elevated liver enzymes, low platelets (HELLP syndrome): consider evolving CAPS
  • LAC conveys the greatest risk for adverse pregnancy outcome (RR 12.15, 95% CI 2.92-50.54) among aPL subtypes. 

Pregnancy losses in general population (non-APS)
· Prevalence of early pregnancy loss: 10-15%
· Prevalence of recurrent early pregnancy loss: 1-2%
· Prevalence of late pregnancy loss (fetal death): 1-2%

—Hematologic

• Thrombocytopenia (22-50%; prevalence varies by definition — mild vs. clinically significant thrombocytopenia)
• Consider screening aPL antibodies in all patients presenting with ITP
• Hemolytic anemia (10%)
• Bone marrow necrosis (rare)
• Thrombotic microangiopathy syndromes (including TTP, HUS)

—Cutaneous

• Livedo reticularis (24%): due to impaired arterial blood flow to skin
  • Persistent, non-reversible with rewarming, violaceous, red/blue, reticular/mottled skin of trunk, arms or legs, consisting of regular unbroken circles (livedo reticularis) or irregular broken pattern (livedo racemosa)
  • Livedo racemosa (irregular, broken pattern) is the form more specifically associated with APS and pathology, while livedo reticularis (regular, unbroken circles) may be physiological [e.g.: benign physiological livedo due to cold (cutis marmorata) or heat (erythema ab igne)]
• Other
  • Pseudo-vasculitic lesions, acrocyanosis, anetoderma, superficial phlebitis, necrotic ulcers, digital gangrene

—Neurological

• Stroke (13%), TIA
• Other manifestations
  possibly related to microvascular thrombosis or direct aPL-related injury to neuronal tissue
  • Chronic headache/migraine (common, >20%)
  • Epilepsy (7%), Cerebellar ataxia (1%), Chorea
  • Visual disturbances
  • Cognitive dysfunction of varying severity
  • Myelopathy, multiple sclerosis-like syndrome
• Sneddon syndrome: widespread livedo reticularis with association with stroke and aPL

—Cardio-respiratory 

• Thrombotic
  • Cardiac: increased coronary artery disease, MI (5%)
  • Respiratory: acute or chronic pulmonary thromboemobolic disease, pulmonary hypertension
• Non-thrombotic
  • Cardiac Valvulopathy:
    • Cardiac valvulopathy: thickening, vegetations (‘Libman-Sacks endocarditis’) (15-30%)
      Most often mitral followed by aortic valve
    • Cardiomyopathy (3%)
  • Respiratory
    • Pulmonary hypertension (2%), alveolar hemorrhage, ARDS, fibrosing alveolitis

—Renal

• Varied: from chronic insidious hematuria/proteinuria (mild to nephrotic) ± declining renal function to acute renal injury  and severe hypertension
• Diagnosis of renal APS is ideally supported by renal biopsy
• Macrovascular
  • Renal artery stenosis, renal venous thrombosis
• Microvascular
  • APS nephropathy
    • Acute: thrombotic microangiopathy of glomerular capillaries
    • Chronic: fibrous intimal hyperplasia, tubular atrophy, arteriolar occlusions, focal cortical atrophy
  • Lupus nephritis
    • If comorbid SLE, might get concomitant immune complex mediated lupus nephritis
    • Biopsy is important here to guide treatment by differentiating inflammatory vs. thrombotic lesions (requiring immunosuppression versus anticoagulation)

CATASTROPHIC APS (CAPS)

Rare (<1%) life-threatening form of APS characterized by (near-)simultaneous micro/macro-vascular thrombosis in multiple organs

—Population

• Sex: 69% female
• Age: Mean age 38 years-old
• Precipitating factor in ~65%
  • Infection
  • Pregnancy (often with HELLP)
  • Surgery
  • Malignancy
  • Anticoagulation interruption/inadequacy
  • Medications (ex: estrogens)
  • SLE flare

—Associated Diseases

• No associated autoimmune disease: ~60%
• SLE-associated: ~30%
• Other autoimmune disease (including ‘SLE-like’): ~10%”
• De novo thrombosis without prior history of thrombosis: 46%

—Thrombotic Features

• Acute (simultaneously or within a week) thrombosis in 3 or more organs, systems, and/or tissues
• Typically small-vessel thrombosis; large vessels can also be occluded
• Organ involvement:
  • Renal (73%)
    • Macro or micro-thrombosis
    • Frequently includes hypertension (often malignant), at risk of requiring dialysis
  • Respiratory (60%)
    • Mostly ARDS and emboli; also: hemorrhage, micro-thrombi, edema, infiltrates
  • Cerebral (56%)
    • Infarcts, encephalopathy, seizure, cerebral venous occlusions
  • Cardiac (50%)
    • Includes valvular disease, myocardial infarction, and myocardial microthrombi
  • Skin
    • Livedo reticularis (47%), livedo racemosa, skin ulcers
  • Other
    • Testicular/ovarian infarction, prostate necrosis, acalculous cholecystitis, bone marrow infarction, esophageal rupture, gastric or colonic ulcer, thrombotic pancreatitis, adrenal infarction

—Inflammatory Features

• Related to systemic inflammatory response and circulating cytokines
• These manifestations may have both thrombotic and inflammatory components, 
• ARDS, encephalopathy, seizures, chorea, longitudinal extensive transverse myelitis, cardiomyopathy

—Laboratory Features

• Thrombocytopenia: ~90%
• DIC (disseminated intravascular coagulation): 11-25% (up to 51% in ICU cohorts)
• MAHA (Microangiopathic hemolytic anemia): 16%

—Diagnosis

Suspect CAPS in a patient (especially a patient with known APS, SLE, or aPL positivity) with multi-system organ dysfunction (particularly ≥3 of lungs, kidneys, liver, brain, heart), onset <1 week, that many plausibly be explained by large vessel or microvascular occlusive disease. There may be a precipitating factor, often infection.

• Supportive labs include
  • CBC, smear, hemolysis markers: Thrombocytopenia, MAHA, schistocytes, elevated reticulocyte count and LDH
  • Serology: aPL positivity
  • Staging: Complete metabolic panel and as-indicated imaging for extent of end organ damage
  • Other: cultures, pregnancy test, ADAMTS13 for TTP, HIT testing, as indicated imaging and adrenal hormones
• Biopsy in select cases of diagnostic uncertainty: showing thrombosis in ≥1 organ or tissue (usually skin, kidney)

—Differential diagnosis

• Disorders associated with microangiopathic hemolytic anemia
  • Sepsis
  • Malignancy
  • Preeclampsia, eclampsia, HELLP syndrome
  • Malignant hypertension
  • Thrombotic microangiopathy: TTP, HUS (Thrombotic thrombocytopenic purpura, Hemolytic uremic syndrome)
  • Drug-related microangiopathic syndromes (i.e. clopidogrel, quinine, chemotherapy…)
  • Heparin-induced thrombocytopenia
  • PNH (Paroxysmal Nocturnal Hemoglobinuria)
• Other disorders: Severe SLE flare, Systemic small vessel vasculitis, paroxysmal nocturnal hemoglobinuria (PNH)
• ADAMTS13 activity testing is critical to distinguish CAPS from TTP
• Anti-PF4 antibodies measured to exclude HIT

—Classification, Treatment

See Below

—Prognosis

• Mortality: 37% (CAPS Registry); improved from ~50% in early series to 25-30% in recent publications with triple therapy
• Cause of death: most often multi-organ failure
• Risk factors for mortality: comorbid SLE
• Survivors of initial CAPS: 66% event-free at 67 months; 19% developed further APS events; 16% died during follow-up.
  No recurrent CAPS episodes were observed.

INVESTIGATIONS

—Baseline Studies

• CBC, smear
  • Baseline for thrombocytopenia, hemolytic anemia, schistocytosis
  • Send direct antiglobulin test, reticulocytes, LDH, depending on suspicion for hemolytic anemia
• Coagulation studies
  • Baseline PT and aPTT; the aPTT may be prolonged due to lupus anticoagulant (found in ~2/3 of patients at presentation), despite the prothrombotic state. PT is typically normal.
• Creatinine, urinalysis
  • Baseline in case of nephropathy
• C3, C4
  • Complement levels may be low in APS patients with comorbid SLE.
  • In primary APS, complement activation products (Bb, C3a) may be elevated and associated with adverse outcomes, but serum C3/C4 levels are not reliably low. Interpret in clinical context.
• Other possible testing, depending on clinical context
  • SLE testing: Clinical evaluation with serology including ANA, ENA, dsDNA
  • Pregnancy test
  • Echocardiogram: if murmur on exam, though valvular disease may be subclinical and consider screening echo more broadly
  • CT pulmonary angiogram, VQ scan: if suspicion for acute/chronic pulmonary emboli
  • CT/MR head and neck: if concern for microvascular cerebral involvement or stroke
  • If ?CAPS, as indicated: full metabolic panel, cultures, pregnancy test, ADAMTS13 for TTP, HIT testing, imaging

—aPL Antibodies

• Types of aPL antibodies
  • Lupus anticoagulant (LAC), commonly caused by underlying antibody to β2GPI or prothrombin
  • Anti-beta2 glycoprotein (anti-β2GPI) antibodies IgG and/or IgM ELISA
  • Anticardiolipin antibodies (aCL) immunoglobulin G (IgG) and/or IgM ELISA
  • “Non-criteria” aPL also exist; less widely used
    • Ex: IgA isotopes of above antibodies, Anti-phosphatidylserine/prothrombin (aPS/PT), Domain-specific anti-beta 2 glycoprotein I, Annexin A5
  • 2023 ACR/EULAR criteria incorporate a weighted laboratory scoring system:
    • Persistent LAC positivity scores highest (5 points for persistent positive, 1 for single positive)
    • aCL/anti-β2GPI IgG ≥40 units scores higher than IgM
    • Isolated IgM positivity alone is insufficient for classification
• Assay Considerations
  • Variability between aPL assays exist worldwide
  • LAC should be performed and interpreted based on ISTH guidelines (International Society of thrombosis and Hemostasis)
  • LAC value is variably affected by anticoagulants (heparin, warfarin, DOACs)
    • DOACs cause frequent false-positive results and LAC should not be tested during DOAC therapy
    • Warfarin may cause false-positive or false-negative results
    • Heparin interference is less problematic with LMWH.
    • aCL and anti-β2GPI ELISA testing is not affected by anticoagulant therapy.
  • LAC positivity is most strongly associated with thrombotic and adverse pregnancy outcomes
  • Anti-β2GPI and aCL should be determined based on standardized ELISA, not other modalities
  • aPL antibodies are associated with a false-positive test for syphilis (VDRL or RPR)
• Other factors causing aPL positivity
  • Infection (usually low-level IgM aCL, not generally associated with thrombosis):
    • Viral: many described, including SARS-CoV-2, HIV, hepatitis B and C
    • Bacterial: any, including bacterial sepsis, TB, syphilis and leprosy
    • Parasitic and fungal: including PJP, malaria
  • Malignancy
    • Solid tumors and hematologic malignancies
  • Medications:
    • Including procainamide, clozapine, phenytoin, valproic acid, TNF inhibitors, hydralazine, propranolol, penicillin, sulfasalazine
• Risk stratification
  • Increased risk of thrombosis in APS
    • LAC positivity
    • IgG over IgM isotype
    • Higher IgG titres
    • Persistent aPL positivity (positive on ≥2 occasions at least 12 weeks apart)
    • Double or Triple positive LAC, aCL, anti-β2GPI (aCL and anti-β2GPI must be high titre, same isotype, and measured at same visit)
  • Risk profiles
    • High risk: Positive LAC +/- moderate-to-high-titer aCL or anti-β2GPI IgG/IgM
    • Moderate risk: Negative LAC with moderate-to-high-titer aCL or anti-β2GPI IgG/IgM
    • Low risk: Negative LAC with low-titer aCL or anti-β2GPI IgG/IgM

DIAGNOSIS

APS should be suspected in a patient, usually younger patient <50 years-old, presenting with at least 1 clinical manifestation of APS and persistently positive aPL antibodies. Clinical manifestations principally include unprovoked venous or arterial thromboembolism (provoked thrombosis has a weaker association with APS but does not exclude it), thrombosis at unusual sites, or pregnancy complicated by thrombosis: pregnancy morbidity (≥3 early losses <10 weeks, ≥1 fetal death ≥10 weeks, severe preeclampsia or placental insufficiency requiring delivery <34 weeks), HELLP syndrome. Other supportive clinical manifestations may include livedo, signs of another systemic autoimmune rheumatic disease, unexplained prolongation of the aPTT, mild thrombocytopenia, renal failure, or Libman-Sacks endocarditis (aka nonbacterial thrombotic endocarditis (NBTE)). Suspect CAPS if multi-system organ dysfunction <1 week, often after trigger (see above). Baseline initial bloodwork should include a CBC, coagulation factors, and basic metabolic panel. Confirmatory aPL antibodies are necessary: LAC, aCL, and anti-β2GPI and should be persistent for more than 12 weeks. It is necessary to consider the strength of association between the thrombosis and aPL, other causes of transient aPL positivity, other non-APS risk factors for thrombosis, and the risk profile of aPL antibodies.

DIFFERENTIAL DIAGNOSIS

• Other Thrombosis risk factors
  • Inherited
    • Factor V Leiden, prothrombin gene mutation, protein C/S deficiency, anti-thrombin deficiency
    • ASH guidelines note that MTHFR polymorphisms should NOT be tested as they have been shown not to be associated with VTE 
  • Acquired
    • Recent surgery, trauma, infection, immobilization, IV drug use
    • Malignancy, myeloproliferative disorders, pregnancy, nephrotic syndrome, CKD, IBD, obesity, smoking
    • Oral contraceptives, heparin (HIT)
    • COVID-19 infection
    • Sickle cell disease
    • Polycythemia vera
• Other Pregnancy risk includes
  • Anatomical: Acquired or congenital uterine abnormalities (ex: leiomyoma, adenomyosis, polyps, Uterine septum)
  • Endocrinological: Hypothyroidism, PCOS, hyperprolactinemia, luteal phase deficiency, and thyroid antibodies
  • Genetic: chromosomal abnormalities in the fetus
• Lifestyle/environmental:
  • Advanced maternal age, smoking, alcohol, caffeine, and obesity are associated with increased miscarriage risk
• Inherited thrombophilia:
  • Factor V Leiden and prothrombin gene mutation have a weak association with recurrent miscarriage
• Other autoimmune diseases with thrombotic manifestations:
  • SLE (independent of APS)
  • Behçet disease (arterial and venous thrombosis)
  • Vasculitis
• Thrombotic microangiopathies:
  • TTP, HUS, and other TMAs (particularly when thrombocytopenia and microangiopathic hemolytic anemia are present)
• Paroxysmal nocturnal hemoglobinuria (PNH):
  • Can present with thrombosis at unusual sites (hepatic, cerebral venous) and should be considered in the differential
• Other Causes of aPL
  • See above, investigations: Including infections, malignancies, and medications
    • Key point: infections (especially viral), malignancies, and medications can cause transient aPL positivity 

CLASSIFICATION CRITERIA: APS

2023 ACR/EULAR CRITERIA, for research purposes

—Entry Criteria

• At least 1 documented clinical criterion from listed below, plus
• A positive aPL within 3 years of the clinical criterion^(b)

—Additive Criteria

• If Entry Criteria present, count following clinical and laboratory criteria below.
• Do not count if there is an equally or more likely explanation than APS
• Within each domain, only count highest weighted criterion

Classify as Antiphospholipid Syndrome if ≥3 points from clinical domains AND ≥3 points from laboratory domains

• (b) aPL positivity must be within ±3 years of the documented (by medical records) clinical criterion.
• (c) High-risk VTE profile is defined based on ≥1 major OR ≥2 minor VTE risk factors
  • Major risk factors (any of, at time of event): Active malignancy, hospital admission, major trauma, surgery
  • Minor risk factor (2 or more, at time of event): Active systemic autoimmune disease or IBD, acute/active infection, central venous catheter, hormonal therapy, travel ≥8 hours, BMI ≥30kg/m², pregnancy/post-partum ≤6weeks, immobilization ≥3 days, surgery with anesthesia <30min within 3 month prior to event
• (c) High-risk CVD profile is defined based on 1 or more high CVD risk factors OR 3 or more moderate CVD risk factors
  • High CVD risk: hypertension (systolic ≥180 mmHg or diastolic BP ≥110 mmHg), eGFR ≤60ml/min, Diabetes with organ damage or long duration (type 1, ≥20 years; type 2, ≥10 years), severe hyperlipidemia
  • Moderate CVD risk: hypertension (systolic ≥140 mmHg or diastolic BP ≥90 mmHg), smoking, diabetes without organ damage or short duration, moderate hyperlipidemia, BMI ≥30kg/m²
• (e) Persistent is ≥12 weeks apart. Consecutive LAC, highest aCL, highest aβ2GPI; if one high and one low consider as moderate

CLASSIFICATION CRITERIA: CAPS

2003 CRITERIA, for research purposes

—Criteria

1. Evidence of involvement of three or more organs, systems, and/or tissues^a
2. Development of manifestations simultaneously or in less than one week
3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue^b
4. Laboratory confirmation of antiphospholipid antibodies (LAC and/or aCL antibodies)^c

—Definite CAPS

• All 4 criteria

—Probable CAPS

• All four criteria, except for only two organs, systems, and/or tissues involved
• All four criteria, except for the absence of laboratory confirmation owing to the early death of a patient never tested for antiphospholipid antibodies before the CAPS
• Criteria (1), (2), and (4)
• Criteria (1), (3), and (4) and the development of a third event between one week and one month after presentation, despite anticoagulation

—Notes

• Biopsy and histological confirmation often not possible due to the critical condition of the patients, a proposal has been made to substitute the “histopathology criteria” by the exclusion of other diagnoses
• (a) Usually clinical evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is 50% rise in serum creatinine, severe systemic hypertension (> 180/100 mm Hg) and/or proteinuria (> 500 mg/24 h).
• (b) For histopathological confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist.
• (c) If the patient had not previously been diagnosed as having an APS, the laboratory confirmation requires that the presence of aPL antibody must be detected on two or more occasions at least 12 weeks apart (not necessarily at the time of the event)

TREATMENT

—Primary Thromboprophylaxis

• Population
  • Patients with only obstetric APS or isolated aPL without APS-related thrombosis
    • Ex: aPL positivity plus: SLE, history of recurrent pregnancy loss, ITP
• Management
  • No anticoagulant-based primary thromboprophylaxis.
  • If: high-risk aPL profile (especially if co-existent SLE or additional cardiovascular risk factors)
    • Some guidelines recommend low-dose aspirin (LDA, ~81mg/d)
  • If: aPL-positive SLE patient
    • Some guidelines recommend hydroxychloroquine and LDA
  • If: surgery, postpartum, prolonged immobilization, or other high-risk situations
    • aPL-positive patients should receive standard thromboprophylaxis with heparin

—First Thrombosis (acutely)

• Definite APS
  • First venous thrombosis: VKA target INR 2-3.
  • First arterial thrombosis: VKA target INR 2-3 (or 3-4, considering individual bleeding/thrombosis risk)
  • Not DOAC, unless allergy/intolerance to VKA or inability to achieve target INR
    • DOACs were associated with a 5.4-fold increased odds of arterial thrombotic events
• Possible APS
  Ex: Possible APS with acute thrombosis but no prior aPL testing, may consider warfarin over DOAC if (opinion)
  • High-risk aPL profile, arterial thrombosis, SLE, prior obstetric APS
  • No acute illness, no alternate explanation for thrombosis, no traditional risk factors

—Secondary Thromboprophylaxis

• Unprovoked
  • VKA long-term, target INR 2-3 (or 3-4, considering individual bleeding/thrombosis risk)
• Provoked
  • May consider stopping after 3-6 months if first thrombosis was clearly provoked AND low-risk aPL profile (e.g., single positive, non-LAC, low titer), in shared decision-making. Most experts favor long-term anticoagulation for definite APS

—Recurrent Thrombosis

• Evaluate medication adherence to VKA and INR at time of recurrent event
• Confirm INR accuracy: aPL can cause artifactual INR elevation, especially with point-of-care devices. Consider chromogenic factor X assay to verify concordance
• If VKA adherent with recurrent thrombosis
  • Consider VKA targeting INR 3-4 if thrombosis occurred while INR was low-end of target range, or
  • Consider switching to LMWH if thrombosis occurred while INR at high-end of target, and
  • Consider adding LDA, hydroxychloroquine, and/or statin
  • Consider adding fondaparinux as an option per CHEST 2021

—Obstetric, during pregnancy

Clinical scenario while pregnant	Management
High-risk aPL profile only (no thrombosis, pregnancy complication)	Consider LDA
“Non-criteria” APS pregnancy complication	Consider LDA or LDA plus prophylactic LMWH (Clinical judgement)
Past delivery <34 weeks due to pre/eclampsia or placental insufficiency	LDA or LDA plus prophylactic LMWH
Obstetric APS only (no thrombotic events)	LDA plus prophylactic LMWH
Recurrent pregnancy complications despite prophylactic LMWH	Consider therapeutic LMWH, +/- HCQ +/- low-dose prednisone in the first trimester.
Pregnant with history of thrombotic APS	LDA and therapeutic LMWH

• Duration: if treated with prophylactic LMWH in pregnancy, continue for 6-12 weeks post-partum
• Warfarin transition. Patients on warfarin should be switched to heparin immediately upon pregnancy confirmation to avoid teratogenicity; best to have planned pregnancy and pre-pregnancy counselling

—CAPS

• Concurrently treat any underlying trigger (example: infection, malignancy)
• If major bleeding, may consider withholding anticoagulation until bleeding ceases
• First Line
  Combination therapy up front for all:
  • Therapeutic unfractionated or LMWH (if suspected HIT, use non-heparin agent), and 
  • Pulse IV methylprednisolone 500-1000 mg/day x 3 days, then prednisone with taper, and
  • PLEX or IVIG (N.B.: obtain aPL measurements first, favour PLEX if TTP-like presentation and AKI)
• Second Line
  • Consider rituximab or eculizumab

PROGNOSIS

• 10-year mortality: 9.3% (10-year survival probability: 90.7%)
• Most frequent causes of death (Euro-Phospholipid 10-year study, n=93 deaths):
  • Severe thrombosis: 36.5% (including MI, stroke, PE)
  • Infections: 27%
  • Malignancy: ~14%
  • Hemorrhage: ~11%
  • SLE-related: ~8%
  • CAPS: ~5%
• Independent predictors of mortality
  • Arterial thrombosis (HR 2.94, 95% CI 1.50-5.76)
  • Concomitant systemic autoimmune rheumatic diseases (HR 2.97, 95% CI 1.56-5.63)
  • Baseline cardiovascular risk factors (HR 2.43, 95% CI 1.05-5.71)
  • Persistent thrombocytopenia  (HR 2.7, 95% CI 1.3-6.0).

REFERENCES

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