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 pre- eclampsia 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 99 th 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
7% 11%28% “EURO- PHOSPHOLIPID” PROJECT Marchetti et al. Clinical and Developmental Immunology Volume 2013, Article ID 159124, 9 pages http://dx.doi.org/10.1155/2013/159124
Catastrophic APLA Rare. Widespread small-vessel thrombosis, multi-organ failure, high mortality. 1. 3 organ/ system involvement 2. Simultaneous/ within a week 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 DD: TTP, DIC
Ruiz-Irastorza et al. The Lancet,376, 9751, 1498 – 1509, October 2010 Inflammation
Thrombosis Antibody +vity: Type, Level, Persistence SLE / NON-SLE ARTERIAL OR VENOUS FIRST OR RECURRENT Modifiable risk factors: HT, Smoking, Cholesterol, OCP
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.13 th 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 20 th 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.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 MFawzy M. Arch Gynecol Obstet. 2013 Sep 19. [Epub ahead of print]Arch Gynecol Obstet.
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 anti2GP1 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.
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.