Transcript Anti-phospholipidAntibody Syndrome

Anti-phospholipid Antibody
Syndrome
Dr Ramesh Jois
Consultant Rheumatologist
Fortis Hospital & Kanva Diagnostics
History
• Conley (1952): Unusual clotting inhibitor causing hemorrhage
in SLE. (Lupus anticoagulant, BFP-STS)
• Bowie (1963): Paradoxically had thrombosis.
• Johansson (1977):”syndrome” of recurrent thrombosis
associated with LAC.
• Nilsson (1975): Recurrent spontaneous abortion might be
associated with LAC.
• Carreras(1981): LAC + Recurrent fetal loss + Thrombosis
• Harris (1983): Solid phase anti-cardiolipin assay.
• McNeill (1990): APL Ab bind diverse protein’s: β2GP-1,
prothrombin (Galli 1990) & phospholipids (Pierangelli 1996).
• Wilson (1999): Classification criteria for APLS.
APLA
Secondary
Primary
Systemic Lupus
Erythematosus.
Rheumatoid arthritis
Scleroderma
Polymyositis
Sjogren’s
APLA Classification Criteria
1. Thrombosis
- Arterial - Stroke / TIA commonly.
Rare: Retinal artery/ Mesenteric/ Coronary/
Pulmonary/ Extremities.
- Venous - DVT/ Central Venous Sinus/
Pulmonary / Retinal Vein/ Superficial Veins/
Unusual site (Axillary, Hepatic, Renal, IVC etc)
- Small vessel – Digital gangrene, Leg ulcers.
APLA Classification Criteria
2.Pregnancy outcomes
- One or more late-term (>10wks) spontaneous
abortion.
- Three or more unexplained, consecutive,
spontaneous abortions before 10 weeks
gestation.
- One or more premature births of a
morphologically healthy neonate at or before 34
weeks’ gestation because of severe preeclampsia or eclampsia or severe placental
insufficiency.
APLA Classification Criteria
3. Laboratory criteria
• Positive: (1) Lupus Anticoagulant
(2) Moderate to high levels of IgG or IgM
anti-cardiolipin antibody (>40GPL/MPL or higher
than 99th percentile)
or
(3) Anti–β2 glycoprotein 1
on at least two occasions at least 12 weeks apart.
One clinical + one lab criterion = Definite
APLS (Classification criteria)
Miyakis et al. J Thromb Haemost.2006;4:295-306
Anti-phospholipid Antibody
• LAC most powerful predictor of thrombosis
(40-fold increased risk of stroke, 5-fold for MI
& increased risk for recurrent miscarriage before 24
weeks) ¹ ²
• LAC –ve APLA +ve : Increased risk of thrombosis &
miscarriage (lesser than LAC +)²
• Anti β2 GP-1: Negative association in 3 systematic
reviews.
Doubled risk for stroke and not MI¹.
• Triple antibody +ve: Highest risk for arterial / venous
thrombosis and obstetric events³
1.Urbanus et al.Lancet Neurol 2009;8:998-1005
2.Opatrny et al.J Rheumatol 2006;33:2214-21
3.Ruffati et al.Arth Care Res.2010;62:302-07
Anti-phospholipid Antibody
• APLA +ve in 30-40% patients with SLE but less than 40% develop
thrombosis¹.
• APLA +ve in 1 in 5 patients with stroke in patients < 50yrs².
• DVT with no SLE: APLA +ve in 24% and LA in 4%³
• 10-15% of women with recurrent miscarriage are APLA +ve⁴.
• APLA +ve in 11-29% of women with PET (compared to 7% in
controls)⁵
• Population-based study : APLA +vity increased risk of PET (OR
2.9) & placental insufficiency (OR 4.58)⁵
• Obstetric APLA: high risk for subsequent thrombotic events.
• 5% healthy individuals are positive for APLA. Clinical risk for
thrombosis is not known.
1. Mok et al.Arth Rheum 2005;52:2774-82 3. Roldan et al.Thromb Res 2009;124:174-77
2. Bushnell et al.Stroke 2000;31:3067-78 4. Rai et al.Human Reprod. 1995;10:2001-05
5. Clark et al.Curr Rheumatol Rep 2007;9:219-25
Marchetti et al. Clinical and Developmental Immunology
Volume 2013, Article ID 159124, 9 pages
http://dx.doi.org/10.1155/2013/159124
7%
28%
11%
“EURO- PHOSPHOLIPID”
PROJECT
Other clinical features
• Thrombocytopenia, Hemolytic anemia (DCT +ve).
• Livedo reticularis (25%) – high risk for arterial
thrombosis.
• Cardiac valve disease - MV > AV, MR > MS,
Asymptomatic.
• Nephropathy – Thrombotic microangiopathy (HT,
non-nephrotic proteinuria, renal impairment).
• Neurologic manifestations: Myelopathy, Chorea,
Epilepsy, Migraine, Cognitive impairment (MR
white-matter lesions).
Catastrophic APLA
• Rare. Widespread small-vessel thrombosis, multi-organ
failure, high mortality.
1. 3 organ/ system involvement
2. Simultaneous/ within a week
DD: TTP, DIC
3. HPE: small vessel occlusion
4. LAC/ aCL + twice 6 wks apart
• Definitive : all 4 criteria
• Probable:
criteria 1,2,4 / criteria 1,3,4
All criteria but 2 organ involvement
All criteria but LAC/ aCL tested
Buciarelii et al. Arth Rheum. 2006;54(8):2568-76
Asherson RA. Medicine (Baltimore).1998;77(3):195-207
Inflammation
Ruiz-Irastorza et al. The Lancet,376, 9751, 1498 – 1509, October 2010
Management
Antibody +vity:
Type, Level,
Persistence
Modifiable risk
factors: HT,
Smoking,
Cholesterol,
OCP
FIRST
OR RECURRENT
Thrombosis
ARTERIAL OR
VENOUS
SLE / NON-SLE
Prevention of recurrent thrombosis –
Secondary Thromboprophylaxis
• Recurrent thrombosis occurs in about 69% over 10
years of observation.
• Recurrences can be prevented by oral
anticoagulation.
• Intensity of anticoagulation is still a matter of debate.
INR 2-3 Vs 3-4.
• High dose steroid + anticoagulation for less severe
catastrophic APS.
• IVIg plus plasmapheresis in addition for severe cases.
Secondary Thromboprophylaxis
• Ruiz-Irartoza et al. Systematic review ¹:
- First venous event: Risk of recurrence
significantly reduced with INR 2-3.
- Arterial or recurrent thrombotic event or both:
risk of recurrence high with INR 2-3; infrequent
recurrence when INR 3-4.
1.Ruiz-Irartoza et al.Arth Rheum 2007;57:1487-95
Recommendations
• Definite APLA: indefinite anticoagulation
- first venous event: INR 2-3
- first arterial event: INR 3-4 or combined antithrombotic
treatment with INR 2-3.
- Recurrent event despite warfarin (INR 2-3): INR 3-4
• Single +ve test / Low-titre APLA (especially with
reversible triggers):
- First venous event: as per standard DVT protocol(3-6m)
- First arterial event: as per standard recommendations
1.Ruiz-Irartoza et al.13th International Congress on APLA. Lupus 2011; 20: 206
Primary prophylaxis
• Still contentious!
- Asymptomatic carriers.
- SLE with antibody positivity.
- Obstetric APLA.
• Reduction of other risk factors for thrombosis.
• Cover high risk situations- surgery, postpartum, long
lasting immobilization etc. (thromboprophylaxis)
• HCQS + Low dose aspirin – SLE with +ve antibody.
• Low dose aspirin or no therapy – Obstetric APLA
• No therapy – Asymptomatic carriers of APLA
Obstetric APLA
•
•
•
•
•
•
Planned pregnancy.
Complete antibody profile.
Screen for LUPUS.
Frequent antenatal visits.
Moniter for PET - HTN, Proteinuria etc.
Fetal surveillance (placental insufficiency) to begin at 32
wks or earlier and continue every week until delivery.
• Uterine and umbilical artery doppler to assess the risk for
PET, Placental insufficiency, Fetal growth restriction.
- After 20th week of gestation; Normal value have high
negative predictive value.
Obstetric APLA
• Heparin started only after confirmation of
pregnancy on ultrasonography.
• Pre-conceptional Aspirin – helpful for
implantation.
• Warfarin – Teratogenic, avoided between 6-12
weeks.
• Steroids – No role.
• IVIg – No role (Pregnancy loss Study Group¹).
1. Am J Obstet Gynecol. 2000 Jan;182(1 Pt 1):122-
Obstetric APLA without Thrombosis
• Recurrent Early (pre / embryonic) miscarriage:
- Aspirin alone or together with LMWH
(prophylactic dose).
• Fetal death (>10 wks) or previous early
delivery (< 34 wks) due to PET or placental
insufficiency:
- Aspirin plus LMWH (prophylactic dose)
Obstetric APLA with previous
thrombosis
• Aspirin plus LMWH (therapeutic dose)
Eg: Enoxaparin 1mg/kg sc 12 hrly
Daltaparin 100U/kg sc 12 hrly
• Monitoring difficult - ?Anti-Factor Xa activity.
Treatment failure in 30% of
APS pregnancies
- Newer Therapies
Does combined prednisolone and low molecular
weight heparin have a role in unexplained
implantation failure?
• A combination of oral prednisolone and low
molecular weight heparin may have a significant
effect on pregnancy and implantation rates in prior
unexplained, failed implantation.
Fawzy M. Arch Gynecol Obstet. 2013 Sep 19. [Epub ahead of print]
HCQS – An old friend with a new role?
• Reduce anti-phospholipid titers in the plasma
of patients with persistent aPL.
• Improve fetal outcomes in SLE treated
pregnant patients.
• Reduces the binding of anti𝛽2GP1 Abs at the
surface of trophoblastic cells.
• Restore the expression of annexin, preventing
pathological activation of trophoblastic cells.
Clinical and Developmental Immunology. Volume 2013, Article ID 159124,
http://dx.doi.org/10.1155/2013/159124
Future Therapies
• Combination anti-aggregant therapy (aspirin + clopidogrel or
dipyridamole): especially when warfarin is contraindicated.
• Oral anti-factor Xa drugs (rivaroxaban, apixaban)
- As effective as warfarin.
• Direct thrombin inhibitors (dabigatran)
- RE-LY trail (AF), RECOVER trial (DVT)
• Statins (fluvastatin, rosuvastatin)
- Inhibhition of tissue factor production by APLA
- Prevent increased adhesiveness of endothelial cell by antiβ2
- Decreased risk of DVT in healthy people with normal
cholesterol (JUPITER)
Summary
• APLA is an important cause of thrombosis and
recurrent pregnancy loss.
• Anticoagulation should be evidence-based.
• Therapy should be individualized.
• Asymptomatic carriers do not need therapy.
• Combined care with Rheumatologist /
Hematologist improves obstetric outcome.
Thank you
Obstetric APLA - Postpartum
• With previous thrombosis:
- Switch to warfarin when clinically stable.
• Without previous thrombosis:
- LMWH (prophylactic dose) for 4-6 weeks or
warfarin.
• Heparin and warfarin – safe for breastfeeding
mothers.
Prevention of pregnancy loss
• No h/o thrombosis/miscarriage-observation/ low
dose aspirin.
• Recurrent early miscarriage- low dose aspirin
• Previous thrombosis- aspirin+ LMW heparin.
• Late foetal loss/ failure of aspirin- LMW heparin+
aspirin.
• Cover post partum period
• Close foetal monitoring and timely delivery-improves
foetal survival.
• Both warfarin and heparin are compatible with
breast feeding.
Variants
• HELLP Syndrome: Haemolysis, Elevated liver
enzymes, Low platelets in women with PET
and positive APLA.
• EVANS Syndrome: Haemolysis with
thrombocytopenia.
Pathogenesis
• Defect in cellular apoptosis---exposes
membrane phospholipids---binds antibody.
• Oxidized β2GP1---Dendritic cell activation--production of autoantibodies.
• Antibodies against prothrombin, Pr C /S.
• Monocyte, Platelet & Endothelial cell
activation.
• Complement activation (pregnancy loss)
Pathogenesis
• Anticardiolipin antibody: against membrane
anionic phospholipids.
• Anti-β2 GP1: Apo-lipoprotein H
(β2glycoprotein) antibodies against domain 1
of β2.
• Lupus anticoagulant: Circulating anticoagulant
Future Therapies
•
-
Hydroxychloroquine
Reduction of thrombosis & cardiovascular deaths.
Platelet activation and clotting inhibition.
Directly inhibits the binding of antiphospholipid
antibody-β2-glycoprotein-1 complexes to phospholipid
surfaces.
- Protective effect of the annexin A5 shield formed over
phospholipid bilayers from damage induced by APLA in
pregnancy.
• B-cell depletion (rituximab) – case reports in severe
disease.