aPS
Antiphospholipid syndrome (aPS) is an autoimmune multisystemic disorder characterized by
recurrent arterial and venous thrombosis and/or pregnancy morbidity associated with the
presence of persistent aPLs (antibodies against anionic phospholipids or protein-
phospholipid complexes).
Epidemiology
Primary aPS is the most common cause of acquired thrombophilia. Accounts for 15-20% of
all episodes of DVT with or without PE, 30% of new strokes occurring in <50yrs and 10-15%
of women with recurrent fetal loss. aPLs are present in 30-40% of SLE patients and 50% of
them will develop aPS (but only 10% of total SLE). 8% of primary aPS patients later develop
SLE. aPLs in <1% of normal people (3% in elderly).
Criteria
Notes
i) only livedo racemosa is scored, reticularis doesn’t count!
ii) in patients with SLE, aPS-nephropathy occurs independent of lesions attributable to LN.
iii) placental insufficiency = IUGR, abnormal Doppler flow at umbilical artery (=fetal
hypoxemia), oligohydramnios, maternal vascular malperfusion on placental histology
iv) valve thickening: MV >4mm (20–39yrs) or >5mm (>40yrs), other valves: >3mm (any age)
vi) 2 consecutive positive results (12 weeks apart) with 1 moderate positive + 1 high positive
aCL/anti-β2GPI should be marked as “moderate positive”.
-Entry criteria: at least 1 clinical criterion + 1 positive aPL (moderate/high) within 3 years of
the clinical criterion
-Classification: 3 points from clinical + 3 points from lab
,Clinical
The clinical consequences include venous and arterial thrombosis, of all sizes of vessels (in
contrast with congenital thrombophilias which are almost exclusively venous) and placental
insufficiency resulting in recurrent fetal loss. However, thrombocytopenia or hemolytic
anemia may occur as the sole manifestation. Although thrombosis is the main clinical
phenotype, major bleeding occurs in 10% (ex. DAH, adrenal hemorrhage) due to capillaritis,
microthrombosis, antiprothrombin antibodies, thrombocytopenia and/or antithrombotic
therapy. The thrombus can be without inflammatory infiltrates.
If aPS affects medium/large vessels → thrombosis.
If arterioles → aPS-vasculopathy.
, •Venous: DVT lower extremities (20-30%), PE (14%), Budd-Chiari, sinus thrombosis
etc. Venous events usually occur at single sites with a tendency to recur in the site as the
original episode.
•Arterial: stroke or TIA (in situ or embolic from valve vegetations), MI (5%), renal
artery thrombosis, glomerular capillary thrombi, digital gangrene. aPLs are (+) in 5-10% of
unselected patients with stroke and in 50% of patients <50yrs with stroke. In case of MI,
they can have microvessel myocardial infarction and the angiography would be normal.
•Thrombocytopenia (15-45%): usually mild (100-150.000), by consumption and/or
destruction. Thrombosis can occur even in the presence of thrombocytopenia. If very low
plts, consider TMA. Criterion if plts<20.000.
• TMA = MAHA + thrombocytopenia + thrombosis + organ damage, but not always.
TMA is a specific histopathologic lesion with i) microthrombi in small vessels (intraluminal
fibrin thrombi), ii) endothelial injury (swelling, ‘endotheliosis’), iii) microangiopathic vessel
wall changes (onion skin intimal hyperplasia), but without any vascular immune deposits.
•Renal:
-hypertension
-renal artery stenosis/ thrombosis, renal vein thrombosis
-aPS-nephropathy (of renal arterioles): triad i) hypertension, ii) proteinuria
>500mg/24h, iii) AKI. TMA is defined histopathologically. Can also be chronic.
-glomerular disease (rare)
•aPS vasculopathy: vessel wall medial hyperplasia and severe luminal narrowing,
endothelial injury, without necessarily thrombus formation, the cause of aPS-nephropathy.
•Anemia: hemolysis
Coombs (-) from TMA [schistocytes (+)]
Coombs (+): 10-20%, spherocytes can be found, but AIHA is relatively
uncommon (an example of non-thrombotic aPS).
•Neurologic (not clearly linked to thrombosis): seizures, transverse myelopathy,
chorea, Guillain-Barré, psychosis, Sneddon syndrome (livedo + stroke), migraines. In addition
to stroke, individuals with aPS can develop white matter lesions on MRI. These lesions are
non-specific and can also develop in other conditions (ex. migraine).
•Cardiac valve abnormalities: the mitral valve is the most frequently involved. Echo
findings include valve thickening, nodules and vegetations. In patients with aPS and a stroke,
we do u/s heart for valvular disease. Despite this high prevalence, only 4-6% of aPL (+)
patients with valve disease will require surgical treatment. Also Libman-Sacks endocarditis.
•Skin lesions: livedo reticularis (most common, but not in criteria), livedo racemosa,
leg ulcers, livedoid vasculopathy (“atrophie blanche”), cutaneous necrosis, gangrene of the
digits or extremities, superficial thrombophlebitis, necrotizing purpura, nailfold infarcts,
ecchymosis (many of them are result of vasculopathy).
Livedo reticularis Dx: sepsis, CTDs, vasculitides, multiple cholesterol
emboli, hyperoxaluria, Sneddon syndrome (livedo + strokes) and healthy.
Livedo racemosa: aPS, Sneddon (stroke + livedo, thrombosis, can be aPL
[+]), livedoid vasculopathy (venous stasis, autoimmune, thrombophilia, neoplasia), PAN,
DADA2, hyperviscocity (essential thrombocythemia, polycythemia vera), TAO.
Leg ulcers Dx: venous insufficiency, atherosclerotic, diabetic foot,
pyoderma gangrenosum, aPS, cryo-vasc, livedoid vasculopathy, PAN, DADA2, calciphylaxis.
•Hemorrhagic manifestations
-DAH is uncommon in aPL (+) patients (<1 %), however, in the setting of
caPS, the frequency is higher (5-10%). Rule out severe mitral regurgitation in case an aPS
patient presents with DAH, as the DAH may be due to PH from an abnormal valve and not
pulmonary capillaritis; treatment in that case is valve replacement and not
immunosuppression.
Antiphospholipid syndrome (aPS) is an autoimmune multisystemic disorder characterized by
recurrent arterial and venous thrombosis and/or pregnancy morbidity associated with the
presence of persistent aPLs (antibodies against anionic phospholipids or protein-
phospholipid complexes).
Epidemiology
Primary aPS is the most common cause of acquired thrombophilia. Accounts for 15-20% of
all episodes of DVT with or without PE, 30% of new strokes occurring in <50yrs and 10-15%
of women with recurrent fetal loss. aPLs are present in 30-40% of SLE patients and 50% of
them will develop aPS (but only 10% of total SLE). 8% of primary aPS patients later develop
SLE. aPLs in <1% of normal people (3% in elderly).
Criteria
Notes
i) only livedo racemosa is scored, reticularis doesn’t count!
ii) in patients with SLE, aPS-nephropathy occurs independent of lesions attributable to LN.
iii) placental insufficiency = IUGR, abnormal Doppler flow at umbilical artery (=fetal
hypoxemia), oligohydramnios, maternal vascular malperfusion on placental histology
iv) valve thickening: MV >4mm (20–39yrs) or >5mm (>40yrs), other valves: >3mm (any age)
vi) 2 consecutive positive results (12 weeks apart) with 1 moderate positive + 1 high positive
aCL/anti-β2GPI should be marked as “moderate positive”.
-Entry criteria: at least 1 clinical criterion + 1 positive aPL (moderate/high) within 3 years of
the clinical criterion
-Classification: 3 points from clinical + 3 points from lab
,Clinical
The clinical consequences include venous and arterial thrombosis, of all sizes of vessels (in
contrast with congenital thrombophilias which are almost exclusively venous) and placental
insufficiency resulting in recurrent fetal loss. However, thrombocytopenia or hemolytic
anemia may occur as the sole manifestation. Although thrombosis is the main clinical
phenotype, major bleeding occurs in 10% (ex. DAH, adrenal hemorrhage) due to capillaritis,
microthrombosis, antiprothrombin antibodies, thrombocytopenia and/or antithrombotic
therapy. The thrombus can be without inflammatory infiltrates.
If aPS affects medium/large vessels → thrombosis.
If arterioles → aPS-vasculopathy.
, •Venous: DVT lower extremities (20-30%), PE (14%), Budd-Chiari, sinus thrombosis
etc. Venous events usually occur at single sites with a tendency to recur in the site as the
original episode.
•Arterial: stroke or TIA (in situ or embolic from valve vegetations), MI (5%), renal
artery thrombosis, glomerular capillary thrombi, digital gangrene. aPLs are (+) in 5-10% of
unselected patients with stroke and in 50% of patients <50yrs with stroke. In case of MI,
they can have microvessel myocardial infarction and the angiography would be normal.
•Thrombocytopenia (15-45%): usually mild (100-150.000), by consumption and/or
destruction. Thrombosis can occur even in the presence of thrombocytopenia. If very low
plts, consider TMA. Criterion if plts<20.000.
• TMA = MAHA + thrombocytopenia + thrombosis + organ damage, but not always.
TMA is a specific histopathologic lesion with i) microthrombi in small vessels (intraluminal
fibrin thrombi), ii) endothelial injury (swelling, ‘endotheliosis’), iii) microangiopathic vessel
wall changes (onion skin intimal hyperplasia), but without any vascular immune deposits.
•Renal:
-hypertension
-renal artery stenosis/ thrombosis, renal vein thrombosis
-aPS-nephropathy (of renal arterioles): triad i) hypertension, ii) proteinuria
>500mg/24h, iii) AKI. TMA is defined histopathologically. Can also be chronic.
-glomerular disease (rare)
•aPS vasculopathy: vessel wall medial hyperplasia and severe luminal narrowing,
endothelial injury, without necessarily thrombus formation, the cause of aPS-nephropathy.
•Anemia: hemolysis
Coombs (-) from TMA [schistocytes (+)]
Coombs (+): 10-20%, spherocytes can be found, but AIHA is relatively
uncommon (an example of non-thrombotic aPS).
•Neurologic (not clearly linked to thrombosis): seizures, transverse myelopathy,
chorea, Guillain-Barré, psychosis, Sneddon syndrome (livedo + stroke), migraines. In addition
to stroke, individuals with aPS can develop white matter lesions on MRI. These lesions are
non-specific and can also develop in other conditions (ex. migraine).
•Cardiac valve abnormalities: the mitral valve is the most frequently involved. Echo
findings include valve thickening, nodules and vegetations. In patients with aPS and a stroke,
we do u/s heart for valvular disease. Despite this high prevalence, only 4-6% of aPL (+)
patients with valve disease will require surgical treatment. Also Libman-Sacks endocarditis.
•Skin lesions: livedo reticularis (most common, but not in criteria), livedo racemosa,
leg ulcers, livedoid vasculopathy (“atrophie blanche”), cutaneous necrosis, gangrene of the
digits or extremities, superficial thrombophlebitis, necrotizing purpura, nailfold infarcts,
ecchymosis (many of them are result of vasculopathy).
Livedo reticularis Dx: sepsis, CTDs, vasculitides, multiple cholesterol
emboli, hyperoxaluria, Sneddon syndrome (livedo + strokes) and healthy.
Livedo racemosa: aPS, Sneddon (stroke + livedo, thrombosis, can be aPL
[+]), livedoid vasculopathy (venous stasis, autoimmune, thrombophilia, neoplasia), PAN,
DADA2, hyperviscocity (essential thrombocythemia, polycythemia vera), TAO.
Leg ulcers Dx: venous insufficiency, atherosclerotic, diabetic foot,
pyoderma gangrenosum, aPS, cryo-vasc, livedoid vasculopathy, PAN, DADA2, calciphylaxis.
•Hemorrhagic manifestations
-DAH is uncommon in aPL (+) patients (<1 %), however, in the setting of
caPS, the frequency is higher (5-10%). Rule out severe mitral regurgitation in case an aPS
patient presents with DAH, as the DAH may be due to PH from an abnormal valve and not
pulmonary capillaritis; treatment in that case is valve replacement and not
immunosuppression.
