4APLA 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.
5APLA 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.
6APLA Classification Criteria 3. Laboratory criteria Positive: (1) Lupus Anticoagulant(2) Moderate to high levels of IgG or IgManti-cardiolipin antibody (>40GPL/MPL or higher than 99th percentile) or(3) Anti–β2 glycoprotein 1on at least two occasions at least 12 weeks apart.One clinical + one lab criterion = DefiniteAPLS (Classification criteria)antiphosphatidylserineantibodies, a type of aPL that is not partof the definition of APS, were responsible for syncytiotrophoblastfusion impairmentsMiyakis et al. J Thromb Haemost.2006;4:
7Anti-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 ²LAC –ve APLA +ve : Increased risk of thrombosis & miscarriage (lesser than LAC +)²Anti 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 events³Dutch case-control study ref 131.Urbanus et al.Lancet Neurol 2009;8:2.Opatrny et al.J Rheumatol 2006;33:3.Ruffati et al.Arth Care Res.2010;62:302-07
8Anti-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%³10-15% of women with recurrent miscarriage are APLA +ve⁴.APLA +ve in 11-29% of women with PET (compared to 7% in controls)⁵Population-based study : APLA +vity increased risk of PET (OR 2.9) & placental insufficiency (OR 4.58)⁵Obstetric APLA: high risk for subsequent thrombotic events.5% healthy individuals are positive for APLA. Clinical risk for thrombosis is not known.24% of 4494 patients with venous thromboembolism in whom a thrombophilia test was done had antiphospholipid antibodies,21Mok et al.Arth Rheum 2005;52: Roldan et al.Thromb Res 2009;124:174-77Bushnell et al.Stroke 2000;31: Rai et al.Human Reprod. 1995;10:5. Clark et al.Curr Rheumatol Rep 2007;9:219-25
9Marchetti et al. Clinical and Developmental Immunology Volume 2013, Article ID , 9 pages7%28%11%in the “Euro-Phospholipid”project on 1000 patients, stillbirths affects up to 7% of APS pregnancies. In the same study, IUGR due to placentalinsufficiency affected 11% of pregnancies and prematuritywasfound in 28% of pregnancies.“EURO- PHOSPHOLIPID”PROJECT
16Prevention 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.
17Secondary 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:
18Recommendations Definite APLA: indefinite anticoagulation - first venous event: INR 2-3first arterial event: INR 3-4 or combined antithrombotic treatment with INR 2-3.Recurrent event despite warfarin (INR 2-3): INR 3-4Single +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 recommendationsResults from observational studies have consistently shown a protective effect of aspirin in asymptomatic antiphospholipidAntibody carriers with systemic lupus erythematosus13,71,77–79 and in women with obstetric antiphospholipid syndrome 44Without treatment chances of successful pregnancy are around 30%, 50% with LDA alone, and up to 70% with both1.Ruiz-Irartoza et al.13th International Congress on APLA. Lupus 2011; 20: 206
19Primary 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 APLANo therapy – Asymptomatic carriers of APLASLE with antibody positivity: LAC OR MEDIUM-HIGH TITRE APLA
20Obstetric 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.Uterine and umbilical artery doppler widely used in EUROPE.
21Obstetric APLAHeparin 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).Am J Obstet Gynecol. 2000 Jan;182(1 Pt 1):122-A multicenter treatment trial of intravenous immune globulin is feasible. In this pilot study intravenous immune globulin did not improve obstetric or neonatal outcomes beyond those achieved with a heparin and low-dose aspirin regimen. Although not statistically significant, the findings of fewer cases of fetal growth restriction and neonatal intensive care unit admissions among the intravenous immune globulin-treated pregnancies may warrant expansion of the study.1. Am J Obstet Gynecol. 2000 Jan;182(1 Pt 1):122-
22Obstetric 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)
23Obstetric APLA with previous thrombosis Aspirin plus LMWH (therapeutic dose)Eg: Enoxaparin 1mg/kg sc 12 hrlyDaltaparin 100U/kg sc 12 hrlyMonitoring difficult - ?Anti-Factor Xa activity.
25Treatment failure in 30% of APS pregnancies - Newer Therapies
26Does 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]
27HCQS – An old friend with a new role? Reduce anti-phospholipid titers in the plasma of patients with persistent aPL.Improve fetal outcomes in SLE treatedpregnant patients.Reduces the binding of anti𝛽2GP1 Abs at the surface of trophoblastic cells.Restore the expression of annexin, preventing pathological activation of trophoblastic cells.the expression ofannexin A5, an anticoagulant molecule normally present atthe trophoblastic cell surface, is reduced by anti𝛽2GP1 Abs.HCQ has been shown to restore its expression, preventingthe pathological activation of the trophoblastic cells . Wealso have demonstrated that HCQ restored the effects ofanti𝛽2GP1 Abs on BeWo cell differentiation and decreasedTLR 4 expression (manuscript under submission).Clinical and Developmental Immunology. Volume 2013, Article ID ,
28Future TherapiesCombination 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 APLAPrevent increased adhesiveness of endothelial cell by antiβ2Decreased risk of DVT in healthy people with normal cholesterol (JUPITER)combination treatment with aspirin plus dipyridamole and aspirin plus clopidogrel have shown higher efficacythan has aspirin alone in patients with stroke106 or atrial fibrillation,107 respectively. Such combinations might be considered in selected patients with antiphospholipidsyndrome in whom warfarin is not eff ective or safe. Likewise, studies of new oral antifactor Xa and antifactor IIa drugs have not been done in patients with antiphospholipid syndrome.108 Rivaroxaban and dabigatran have been licensed for primary thromboprophylaxisafter orthopaedic surgery in many settings.The results of the RE-LY trial, done in patients with atrial fibrillation at high risk for arterial thromboembolism, showed that dabigatran, at a dose of 110 mg twice daily is as effective but safer than warfarin, whereas doses of150 mg twice daily are more eff ective and equally safe.109 Data of the RE-COVER study,110 comparing dabigatran 150 mg twice daily with warfarin in the treatment of acute venous thrombo embolism after heparin treatment, showed an equivalence of both therapies in relation to efficacy and toxic effects.110 One of the major advantages of dabigatran and rivaroxaban is that regular blood tests are not needed to monitor the anticoagulant effect.However, both are limited by the inability to reverse their anticoagulant eff ect. B-cell depletion therapy with the chimeric monoclonalantibody rituximab has been tested in patients with severe forms of antiphospholipid syndrome. Experience is limited to case reports; however, a high response rate—more than 90%—has been recorded.111Fluvastatin inhibits tissue factor production induced by antiphospholipid antibodies both in mice models113 and in cultured human endothelial cells.114 Statins also prevent the increased adhesiveness of endothelial cells inducedby anti-β2-glycoprotein In a pilot trial with fl uvastatin in nine patients with antiphospholipid syndrome, fluvastatin at 40 mg per day decreased the concentrations of infl ammatory and thrombogenic mediators after 30 days of treatment.116Moreover, data from the JUPITER trial showed a decreased risk of venous thromboembolism in healthy people with normal cholesterol concentrations given rosuvastatin.118A reduction of thrombosis and cardiovascular deaths has been recorded in lupus patients taking antimalarial drugs.119 Observational studies have suggested an antithrombotic effect of hydroxychloroquine in patients with antiphospholipid antibodies, most of whom have systemic lupuserythematosus.19,71,120 Furthermore, results from basic studies have shown a dose-dependent reduction byhydroxychloroquine of platelet activation and clottinginduced by antiphospholipid antibodies.121,122 Hydroxychloroquinedirectly inhibits the binding of antiphospholipidantibody-β2-glycoprotein-1 complexesto phospholipid surfaces.123 An additional and previouslyunrecognised role of hydroxychloroquine in preventionof pregnancy loss is suggested by the description of itsprotective eff ect of the annexin A5 shield formed overphospholipid bilayers from damage induced byantiphospholipid antibodies.124
29SummaryAPLA 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.
31Obstetric 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.
32In vitro action of lupus anticoagulant In vitro action of lupus anticoagulant. Antiphospholipid antibodies responsible for the lupus anticoagulant test are believed to act at the level of the 'prothrombin activator complex' of the clotting cascade. For prothrombin to be converted to thrombin, a complex of factors Xa, V and prothrombin must be formed on a phospholipid template in the presence of calcium. Antiphospholipid antibodies may bind the prothrombin–phospholipid complex; disrupt the complex and so delay prothrombin-to-thrombin conversion. This will result in a delay of fibrin formation and prolongation of coagulation tests.
33Prevention of pregnancy loss No h/o thrombosis/miscarriage-observation/ low dose aspirin.Recurrent early miscarriage- low dose aspirinPrevious thrombosis- aspirin+ LMW heparin.Late foetal loss/ failure of aspirin- LMW heparin+ aspirin.Cover post partum periodClose foetal monitoring and timely delivery-improves foetal survival.Both warfarin and heparin are compatible with breast feeding.
34Demonstration by MRI of biparietal infarctions in a 26-year-old woman with antiphospholipid syndrome. This woman also had a right frontal lobe infarct, which is not shown here. She had no risk factors for thrombosis other than the lupus anticoagulant and high positive IgG anticardiolipin antibodies. Her first pregnancy was terminated with intrauterine fetal death at 24 weeks gestation.
35VariantsHELLP Syndrome: Haemolysis, Elevated liver enzymes, Low platelets in women with PET and positive APLA.EVANS Syndrome: Haemolysis with thrombocytopenia.
36PathogenesisDefect 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)
37PathogenesisAnticardiolipin antibody: against membrane anionic phospholipids.Anti-β2 GP1: Apo-lipoprotein H (β2glycoprotein) antibodies against domain 1 of β2.Lupus anticoagulant: Circulating anticoagulant
38Future 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 overphospholipid bilayers from damage induced by APLA in pregnancy.B-cell depletion (rituximab) – case reports in severe disease.