Antiphospholipid antibody and syndrome (APLA and APS) Flashcards
Antiphospholipid antibodies (APLAs) are heterogenous group of antibodies that bind to __ with affinity for __ (which most antigens are involved in coagulation)
ALPAs (3+1)
Antiphospholipid syndrome (APS) is the clinical manifestation of either __ or __ with presence of __
Plasma protein, affinity for phospholipid surfaces
APLAs
1. Lupus anticoagulant (LAC)
2. Anticardiolipin Ab (ACL Ab)
3. Anti-beta-2 glycoprotein I Ab (B2GP1)
4. Anti-phosphatidylserine-dependent prothrombin Ab (anti-PS/PT)
APS:
- Vascular thrombosis or pregnancy morbidity
- Presence of APLAs
How are APLAs measured?
- LA
- Phospholipid dependent screening assay -> prolonged
- Mixing test - does not correct - ACL Ab - ELISA IgM, IgG
- Anti-B2GP1 - ELISA IgM, IgG
- Anti-PS/PT - ELISA IgM, IgG
Value of false positive VDRL
VDRL measures agglutination of lipid particles that contain cholesterol and negatively charged phospholipid cardiolipin
APLAs bind to cardiolipin, causing agglutination and indistinguishable from syphilis
False positive VDRL or RPR seen in 50% of patients with APLAs
What are the significance of positive APLAs?
And when should we suspect APS?
Low titres of ACL in 5-10%; LAC in 1% healthy population
- < 1% persistently positive when retested
- Occurs de-novo or associated with autoimmune disease, infections, medications and malignacy (lymphoma)
Positive APLAs may predict increased risk for:
1. Stroke
2. VTE
3. Recurrent fetal loss
APS suspected if there is:
1. Arterial thrombosis < 50 years old
2. Unprovoked VTE < 50 years old
3. Recurrent thrombosis
4. Combined arterial and venous thromboembolism
5. Thrombosis at unusual sites - renal, hepatic, cerebral sinus, mesenteric, vena cava, retinal, subclavian
6. Recurrent fetal loss or miscarriages, severe or early pre-eclampsia, IUGR, HELLP
What is the 1-in-5 rule of APS?
- 20% of unprovoked DVT
- 20% of young adult stroke
- 20% of miscarriages/placental ischaemia
International Consensus Classification Criteria for APS
At least 1 clinical criteria:
1. Vascular thrombosis not due to another cause
2. Pregnancy morbidity
- 1 or more unexplained miscarriage > 10 weeks of gestation
- 1 or more premature birth < 34 weeks gestation due to pre-eclampsia or placental insufficiency
- 3 or more unexplained miscarrriages < 10 weeks, excluded anatomical, hormonal and chromosomal cause
At least 1 laboratory criteria (on 2 or more occasions, 12 weeks apart, not more than 5 years):
1. ACL moderate or high titre
2. Anti-B2GP1 elevated
3. Positive LAC without coagulopathies or DOAC use
What are supportive manifestations of APS that are not included in the APS criteria?
Clinical manifestations
1. Valvular heart disease
2. Neurologic conditions (chorea, seizure, cognitive dysfunction)
3. Nephropathy (acute thrombosis, vaso-occlusive disease)
4. Dermatologic (livedo reticularis, levedoid vasculopathy)
5. Pulmonary (PHT, DAH, fibrosing alveolitis)
6. Avascular necrosis
Laboratory manifestations
1. Hematologic (thrombocytopenia, MAHA or AIHA)
2. Other antibodies
- Annexin
- PS/PT
- Protein C/S
- Vimentin/cardiolipin complex
Primary APS (PAPS) is the presence of __ in setting of __ without another __
It is also known as __
Secondary APS (SAPS) occurs in about __% of patients with __ and __
Commonest autoimmune disease: __
Alternatively, 40-50% SLE patients have APLAs and is a criteria for SLE diagnosis
However, only ____% SLE patients with APLAs develop thrombotic event each year
PAPS
APLAs in thrombosis without another associated disease
Hughes syndrome
SAPS
50% patients with associated rheumatic disease with APLAs
Commonest in SLE
Only 3-7% SLE patients develop SAPS each year
What are conditions associated with increased APLAs production? (MAIN)
M: medications
- Chlorpromazine
- Procainamide
- Quinidine
- Hydralazine
- Phenytoin
- Alpha interferon
- IL2
- TNF-alpha inhibitors
A: autoimmune
- SLE (40-50%)
- RA
- Dermatomyositis
- Sjogren’s syndrome
- Systemic sclerosis
I: infection
- Bacterial or viral
- Hepatitis C, HIV
N: neoplasm
- Lymphoma
Does LAC affect PT and APTT?
PT - newer assays are not affected
(However if PT is prolonged, there is possibility of extremely high LAC or antibodies against factor II prothrombin, which increases risk of haemorrhage when anticoagulated)
APTT - 50% LAC have prolonged APTT
Confirmatory test for LAC
drVVT
STACLOT-LA
Is there such thing as seronegative APS?
Yes, very rare and not formally acknowledged
Mandatory criteria:
Excluded all other causes of inherited hypercoagulable state
Possible reasons:
1. Overtly large clots might consume all APLAs into the clot - false negative
(repeat test in 12 weeks might turn positive)
2. Other pathogenic APLAs that are not tested (not in criteria)
3. Domain I-B2GP1 not detected on ELISA
(To also test IgA)
What are the second hit factors that increases risk of thrombosis in APLAs?
A. Antibody characteristics
1. Triple positives: LAC + ACL + AB2GP1
2. IgG with AB2GP1 reactivity against first domain
3. High titre APLAs > 40 units
4. LAC
B. Tissue factor release - infection, surgery
C. Endothelium dysfunction
1. SLE or vasculitis
2. Atherosclerosis and risks (DM, HLD, HTN)
3. Angiogram or even IV access
D. Prothrombotic rsks
1. Smoking
2. OCP
3. Pregnancy
4. Homocystinaemia - MTHFR mutation A1298C
5. Hereditary hypercoagulable state - FV leiden, protein C/S deficiency, prothrombin gene mutation, AT3 deficiency
6. History of thrombosis or fetal loss
7. COX-2 inhibitor use
Clinical features of APS (CLOT)
C: clot - recurrent arterial/venous thrombosis
L: livedo reticularis exagerrated by cold
O: obstetrical complications - miscarriage, IUGR, PE
T: thrombocytopenia
What are the risk of thrombosis in APS?
Risk: LAC > ACL and AB2GP1
(In triple positives - OR 34.4)
VTE (OR 11)
Stroke (OR 8.1)
Fetal loss (OR 7.8)
Thrombosis in SLE (OR 5.6)
Organ thrombotic manifestations in APS
- CNS - recurrent stroke, cerebral sinus thrombosis
- Eye - ischaemic optic neuropathy, blindness
- Spine - transverse myelitis
- Skin - digital gangrene or cutaneous ulceration
- Renal - renal artery/vein thrombosis, renal failure
- Pulmonary - pulmonary embolism, pulmonary hypertension
- Liver - Budd-Chiari syndrome
- Heart - SVCO, subclavian vein thromobsis
- Endocrine: adrenal infarct, pituitary infarct
- Bones - avascular necrosis
What other clinical manifestations are associated with APS?
- Migraine headache
- Seizure
- Livedo reticularis
- Valve disease - mitral > aortic, vegetations
(Severe MR may cause DAH due to pulmonary hypertension - treatment is valve replacement, not immunosuppression) - Atherosclerosis
- Thrombocytopenia and thrombotic microangioapthy
- Haemolytic anaemia - Coombs positive
Microangioapthy and microvascular thrombosis with APS (MAPS) involves __ in visceral organs
Pathogenesis:
1. __ with or without __ causing ischaemia and microinfarcts
2. Endothelial injury to microvessels leading to __
(schistocytes, high LDH, severe thrombocytopenia)
Small vessels
- Endothelial proliferation with or without clot
- MAHA (microangiopathic haemolytic anaemia)
Catastrophic antiphospholipid syndrome (CAPS) is also known as __
- Occurs in __% of patients with APS, however __% as initial presentation of APS
- Involves __ or more organs (onset: __ or within __)
- Precipitated by: __
- Histology: ___
Organ manifestations: (5)
Blood manifestations (2)
Differentials: (4)
Prognosis: __
Asherson’s syndrome
- < 1% of patients, however 50% comes as initial presentation of APS
- 3 or more organs (onset: simultaneous or within 1 week)
- Precipitated by: unknown (45%), infection (20%), surgery (14%)
- Histology: small vessel thrombosis
Organ manifestations
1. Cardiopulmonary - respiratory failure, haemorrhage
2. CNS manifestation
3. Abdominal pain
4. Renal failure
5. Cutaneous disease
Blood manifestations
1. Thrombocytopenia
2. Haemolytic anaemia
Differentials:
1. TTP / HUS
2. Malignant hypertension
3. DIC
4. HELLP
Prognosis: 30-50% mortality, with 33% recurrent thrombosis in 5 years even with adequate anticoagulation
Primary thrombosis prevention in APLAs without any complications (no thrombus, no pregnancy issues)
- Low dose aspirin - controversial
- APLASA 2007 - no benefit from low dose aspirin
However preferred if high risk factors:
- Triple positive, double positive
- SLE patients
- Calculated Framingham’s score > 10%
- Mitigate modifiable risk factors - smoking, HLD, HTN, DM, immobility, birth control pill
- SC LMWH prophylaxis for flight >4-8 hours
- Also to ambulate and perform calf exercises mid flight
Post-operative management
1. Compression stockings and early ambulation post-procedures
2. SC LMWH at least 1 week up to 6 weeks
Treatment for APS
How about initial treatment options for APS with HIT
APS without HIT
1. UFH (higher risk for HIT) or
2. LMWH (lower risk for HIT, osteoporosis)
3. Switch to warfarin
APS with HIT - initial treatment then to warfarin
1. Direct thrombin IIa inhibitor - argatroban
- Treatment: IV 2 mcg/kg/min
- Monitor PTT when transitioning to warfarin
- Dose adjust in liver failure
or
- Synthetic pentasaccharide - fondaparinux
- Treatment: SC 7.5mg (> 50kg) or 10mg (>100kg) Q24H
- Monitor anti-factor Xa level 4 hours after dose
- CI in CrCl < 30
