2 Prof. Dr. Suchitra N. Pandit MD, DNBE, DFP, FRCOG, FICOG, B.PharmConsultant Obstetrician & GynaecologistKokilaben Dhirubhai Hospital, Mumbai ,IndiaClinical secretary –MOGS, Vice President - FOGSI ( )Chairperson -Young Talent promotion committee FOGSI ( )
3 Antiphospholipid ( APLA ) syndrome Antiphospholipid syndrome (Hughes syndrome) is adisorder of immune system ,characterised by excessive clotting of blood ,thrombocytopenia & /or adverse pregnancy outcomesBody recognizes negatively charged phospholipids on cell membrane as foreign & produces antibodies against them leading to an acquired autoimmune thrombophiliaPatients have laboratory evidence for antibodies ( IgG, IgM or IgA ) against phospholipids or phospholipid-binding protein cofactors in their blood
4 How many types of APLA syndromes are there A.) OneB.) twoC.) ThreeD.) Four
5 Antiphospholipid antibody syndrome (APLA) Primary antiphospholipid syndrome (PAPS) - when APS occurs in the absence of any other related disease (LA, ACL antibodies in patient’s serum).Secondary antiphospholipid syndrome - when APS coexists with other diseases such as SLE IIn catastrophic APLA (rare ), APS leads to rapid organ failure due to generalised thrombosis & a high risk of deathOther rare antibodies to phosphotidyl ethanolamine & phosphotidylserine are also associated with it
6 either acquired or inherited Thrombophilic defectseither acquired or inherited
8 Inherited Hyperhomocysteinemia (C677T) mutation Factor V Leiden mutation (A506G) mutationMutation in prothrombin ( G A)Prothrombin II (PTII) mutationProtein S deficiencyProtein C deficiency
9 All these conditions should be investigated for APLA except : A.) Early onset severe preeclampsiaB.) Arterial or venous thrombosisC.) Unexplained fetal growth restrictionD.) Gestational Diabetes
10 Primary antiphospholipid antibody syndrome Presentation may be totally asymptomatic or in a classical manner :Various clinical presentations :Recurrent pregnancy lossUnexplained second or third trimester lossEarly onset severe preeclampsiaArterial or venous thrombosisUnexplained fetal growth restrictionProlonged coagulation studiesAutoimmune diseasesCardiac valvular diseasesNeurological disordersThrombocytopenia
11 Diagnosis of APLA Challenging !!! Due to fluctuating titers of the antibodies,Lack of agreement between laboratories concerning standardization of the assaysDebates among researchers & clinicians concerning which antibodies to measure.
12 Which is not an APLA antibody ? A.) Anti RoB.) Lupus Anticoagulant (LAC)C.) Anticardiolipin Antibodies (ACL)D.) Anti insulin antibodies
13 Which are the Antibodies Lupus Anticoagulant (LAC)Anticardiolipin Antibodies (ACL)Anti Beta 2 glycoprotein antibodiesOther antibodies
15 Lupus anticoagulant ( LAC) LAC is characterized by a prolonged partial thromboplastin time & paradoxically the so-called ‘anticoagulant’ is a powerful thrombotic agent in vivoHigher thrombotic potential than ACL when present aloneLAC interferes with platelet function, causing aggregation & thrombosis & also interferes with endothelial function, causing procoagulant activation & thrombosisPrevalence of LAC in low risk population is < 1% Bad obstetric history % Early pre eclampsia %, Abruption - 33% Systemic lupus erythematosus - 34%
16 Patient typically has a prolonged APTT that does not correct in 80:20 mixture with normal human plasmaProlonged Dilute Russel viper venom time (DRVVT), Kaolin clotting test (KCT),(TDT/DTT) or prothombin timeDue to heterogeneous nature of LA ,minimum of 2 tests required, 6 weeks apart & should be positive each time showing persistent positivity to confirm diagnosis of APLA Caution : patients with transient positive tests (due to infection etc) can be diagnosed as positive.
17 Lupus anticoagulant (LAC) Prolongation of which of these tests is most sensitive for LAC ?A.) Activated partial thromboplastinB.) Dilute Russel Viper venomC.) Kaolin clotting timeD.) Partial Thrombin time
18 Anticardiolipin Antibodies Were thought to react against cardiolipin but it is now thought to interact with B2GP185% of APS pts have both LA & aCLThese can be detected using an (ELISA)Screens for the presence of β2 glycoprotein 1 dependent anticardiolipin antibodies (ACA)A low platelet count & positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis
19 Anti Beta 2 GP1 Discovered after LA & ACL Found without other two in 11% of APS pts & commonly with others.Binds to B2GP1 disrupting f(x)B2GP1 has anticoagulant activity through the inhibition of the conversion of prothrombin-thrombin, regulation of protein S, & /or activation of platelets.
20 Sapporo criteriaInternational Consensus Conference held in Sapporo (’98)Clinical criteria of ( APAS )Thrombosis, one or more confirmed episodesof venous, arterial, or small vessels disease‘ Coexisting inherited or acquired thromboticrisk factors are not reasons for excludingpatients from a diagnosis of APS trials.’
21 Sapporo Criteria (updated) Pregnancy criteria :One or more unexplained fetal deaths > 10 wks of pregnancyOne or more preeclampsia / eclampsia or placentalinsufficiencies occurring before 34 weeks .Three or more unexplained consecutive spontaneousabortions < 10 weeksLaboratory criteriaLAC defined by a functional, clot-based assay (ISTHguidelines)ACL (IgG or IgM) antibodyAnti-b2 glycoprotein I ,IgG or IgM antibodyMiyakis, et al., J. Thromb. Haemost.,2006; 4:
22 The International Consensus Statement Definite CAPS diagnosis requires:Vascular thrombosis in three or more organs or tissues & development of manifestations simultaneously or in < a week & small vessel thrombosis in at least one organ or tissueLab. confirmation of presence of aPLSome serological tests for syphilis may be positive in aPL- positive patients if it is positive) although more specific tests for syphilis that use recombinant antigens are negativeTransient elevations common. Elevations common in autoimmune disease & infections ex. HIV, Hep C, syphilis
23 Principal pathogenic mechanisms mediated by APL Reduction of proliferation & differentiation; Gonadotrophin secretion impairmenta.) Trophoblast cells:Interference with :Induction of a pro-adhesive, pro-inflammatory & pro-coagulant endothelial phenotype ; induction of a procoagulant phenotype in monocytesb.) Coagulation cells: Protein C/S pathway inhibition; fibrinolysis inhibitiona.) Soluble coagulationfactorsInterference with
24 Pregnancy losses classified as : Occult (preclinical or chemical) pregnancy loss prior to missed menses. (40% of implantation embryos)Early pregnancy loss before 12 wk. (13%)Late pregnancy loss after 12 wk. (1%)
25 Causes of pregnancy loss Chromosomal55% of occult & early losses5% of recurrent losses.EnvironmentalhormonalanatomicalImmunological45% of early losses95% of late losses
26 Aneuploidy 1/200 1/80 Aneuploid fetus risk in women > 35yr. age Inherent risk of fetal loss afteramniocentesis1/200Standard of care is to offer genetic amniocentesisfor all pregnant women older than 35 years
27 What is Recurrent pregnancy loss ? What actually causes it ?
28 DefinitionA recurrent pregnancy loss (RPL) is 3 or more consecutive, spontaneous pregnancy losses, under week gestation from the last menstrual period by the same partner.Primary recurrent pregnancy loss" refers to couples that have never had a live birth“Secondary RPL" refers to those who have had repetitive losses following a successful pregnancy
29 Pregnancy loss in the APLA syndrome - A possible thrombogenic mechanism Levels of annexin V, a phospholipid-binding protein with potent anticoagulant activity, are markedly reduced on placental villi from women with APLAAPL antibodies reduce the levels of annexin V & accelerate the coagulation of plasma on cultured trophoblasts & endothelial cells.Reduced annexin V levels on vascular cells may be an important mechanism of thrombosis & pregnancy loss in APLA syndrome.Jacob Rand, Xiao-Xuan Wu, H. Andree, CJ. Lockwood, Seth Guller, J Scher, Peter Harpel, -N Engl J Med ; 337: , 1997
30 Pregnancy loss in autoimmune connective tissue disorders (CTDs) Adverse outcomes like IUGR, prematurity, recurrent pregnancy loss & stillbirth are commonSystemic lupus erythematosus (SLE) is prototype , others are rheumatoid arthritis, scleroderma, Behcet’s disease & Sjogren’s syndromeRecent studies show anti-Ro/SSA antibody as a possible factor for unexplained pregnancy loss in SLE.Antibody is directed against cellular ribonucleoprotein complexes which is present in serum of > 10% pts of CTDs.It is associated with neonatal lupus & congenital heart block showing passively acquired autoimmunity
31 How do you proceed ? Interview the couple together History of the case is very importantClinical examinationInvestigations as per the historyReassurance & counsellingTreatment plan : Drugs, maternal & fetal surveillance , dealing with complicationsTimely referral to a tertiary centre
32 Special Investigations LAC tested by prolonged coagulation time (inhibition of phospholipids)APTT , KCT , TTITMost accurate - Dilute russel viper venom test (DRVVT)ACL - ELISA IgG (GPL) IgM (MPL)IgG/ IgM isotypes of anticardiolipin & antiphosphotidylserine antibodiesIn c/o low titres-repeat after 6-8wks (can revert to normal)Transient low titres can be found in viral feverIf autoimmune disorders are suspected ANA, anti –nDNA, antiSm, anti-Ro/SSA antibody, anti La (SSP)
33 So how does one manage the drug treatment in pregnancy ? General guidelines for anticoagulation in Pregnancy with APS leading to recurrent pregnancy lossVery controversial issue !
34 Commonly used Drugs Steroids : Reduces ACA, normalises prolongation of invitro coagulationComplications : ? perinatal outcome preterm labour,preeclampsiaLow dose Aspirin (LDA) : Selective inhibition ofThromboxane A2No effect on PGI2AzathioprineWarfarin
35 Which is the commonly used drug for APLA ? A.) ProgesteroneB.) Folic acidC.) Low dose AspirinD.) RU- 486
36 Unfractionated Heparin (UFH) Potentiates complex formation with AT III + factor VII A XII A & thrombinComplications : Reduces platelet bleeding &B.M.D.Low molecular weight Heparin (LMWH)Once daily dose, less monitoringLesser osteopenia, does not cross placentaCost factor !!
37 Trials Heparin vs Aspirin + prednisolone Live birth 75% Pre-eclampsia, preterm delivery more in latter groupL.S. + LDA Vs Heparin + LDA (n=20)No placeboLarge multicentric trials neededCowchock et al .1994
38 Randomised controlled trial of LDA versus LDA plus heparin in pregnant women with APS 90 women with APS were randomized into two groups with 1st group receiving 75mg of LDA & 2nd group LDA & Heparin 5000u subcut, every 12 hourlyOutcomes measured were number of live births & miscarriagesLDA group had 19 live births & 26 miscarriagesLDA + heparin group had 32 live births & 13 miscarriagesSignificant (p=0.01) improvement in outcomes with heparinR. Rai, H.Cohen et al..,BMJ. (1997 )
39 Antiphospolipid antibodies Presence of Antiphosholipid antibodies may cause recurrent pregnancy lossAre antibodies directly responsible ?Should all women with APA be treated ?How do you treat a women with positive APLA ?
40 Controversies surrounding treatment for pregnancy loss Evidence-based medicine (EBM) has not succeeded in giving patients & physicians the data they need to choose (or not choose) a therapy in the field of pregnancy loss
41 Women with APLA are advised to take LDA & to start LMWH Rx after pregnancy is diagnosed (80% success)In case of H/o thrombotic symptoms, Warfarin is used as anticoagulant .Maintain INR betweenPatients with APLA have minor elevations of PT & are difficult to manage with warfarin.During pregnancy, LMWH & LDA are preferred to Warfarin (teratogenic effects )If previous H/o thrombosis use LMWH in therapeutic doses throughout pregnancy :dose 1mg/kg subcut.If UFH is used dose is 10,000 u 12 hourly
42 Since APLA reacts with phospholipids both aPTT & PT can be affected Since APLA reacts with phospholipids both aPTT & PT can be affected. If UFH used to anticoagulate patients with APLA monitor heparin levels ( anti-Xa units 6 hours post injectiont ).With LMWH , monitoring is easier : predictable dosing & anticoagulant effect . Measure LMW heparin levels in these patients for long term Rx ( anti-Xa units)Perform prothrombin & proconvertin times ("P&P") to follow anticoagulation. Being less dependent on phospholipids & one can monitor therapy.If miscarriage occurs with heparin & aspirin & there is a pregnancy again IVIG can be tried (RCT did not show benefit)In refractory cases plasmapheresis may be used
43 ACCP Guidelines : Pregnancy & APL ManifestationRecommendationGradeAntiphospholipid antibody; no prior VTE or pregnancy lossSurveillance, or mini-dose heparin, or prophylactic LMWH, & /or aspirin2CAntiphospholipid antibody; prior thrombotic eventAdjusted dose UFH or LMWH, plus low-dose aspirin.1C- Bates, et al., Chest, 2004; 126: 627S - 644S
45 Management of pregnant women Surveillance depends on past obstetric historyLDA preconception & LDA + LMWH has 80% success rate for treatment of APLA ( Feinberg et al,’ 97 ).Refer preferably to a tertiary centre with a neonatal backupTeam effort including an obstetrician , hematologist, physician, & neonatologistVigilant monitoringB.P, platelets, complement levels , renal function test (to asses target organ damage )
46 Care of the fetus Surveillance depends on past obstetric history 1st trim U.S.G : viability & dating , nuchal & nasal boneU.S.G at 19 weeks & serial scans with doppler for early diagnosis of IUGR & waveform abnormalitesInj Betamethasone 2 doses for enhancing lung maturityTimely delivery in a centre with a good neonatal backup
47 Future Possibilities PAPRE warfarin intensity PRECLUDE primary preventionMore frequent use of LMWH, IVIG
48 What to do with the patient with APLA but no thrombotic manifestations ? Although some of these patients are at risk, especially those with SLE, many will never develop thrombosisThe current recommendation would be to do very careful search for thrombosis. Brain MRI in patients with SLE & in patients with any neurological symptomIf this work-up is negative follow the patient very closelyDoes immunosuppression work ?APLA seems like an autoimmune disease, but immunosuppression does not prevent recurrent thrombosis, fetal loss, or neurological syndromes & so no role in the Rx of thrombotic APLA
49 In"catastrophic APLA" plasmapheresis may play a crucial role. Low intensity anticoagulation with warfarin appears to be mostly effective in APLA (except patients with venous thrombosis)Many patients will fail low intensity warfarin & need more aggressive anticoagulation.Heparin anticoagulation appears more effective. Arterial Thrombosis: Warfarin to an INR of Venous Thrombosis: Warfarin to an INR of Patients who "break through" warfarin should receive heparin.
51 Inherited Thrombophilia Three important inherited thrombophilias :Mutation in factor V Leiden causing resistance toactivated protein C (responsible of 20–30% of venousthromboembolism events.)Mutation in prothrombin (guanine adenine )Mutation in methylene tetrahydrofolate reductase(MTHFR) (cytosine 677 thymine (C677T) ) Thisis responsible for reduced MTHFR activity & is mostfrequent cause of mild hyperhomocysteinemia &is found in 5–15% of the population.
52 Factor V Leiden (A506G) mutation Present in 3-8% of the general population , (heterozygotes) have a seven fold increased risk for thrombosis whereas homozygotes have an eighty fold increase.It has been linked with an increased risk for venous thromboembolism due to resistance to activated protein C & is responsible of 20–30% of venous thromboembolism events
53 Protein S deficiencyProtein S deficiency (PSD), present in up to 2% of general population.Found in approximately 15% of individuals with a DVT or PE .Found in 6% of women with obstetrical complications including a relatively high risk for stillbirth.
54 MTHFR (C677T) mutationA homozygous (MTHFR) mutation, present in 1-4% of the general population, is associated with a three fold increased risk for DVT or PE, as well as preeclampsia & placental abruption.
55 MTHFR (C677T) mutationResponsible for reduced MTHFR activity results in decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of homocysteine to methionine & the resulting increase in plasma homocysteine concentrations ( Hyperhomocysteinemia ) is a risk factor for thrombosisDietary restriction of folate & vitamin B12 remains the most common cause.
56 Prothrombin (G20210A) mutation A change of G to A at position in prothrombin (prothrombin 20210A) elevates baseline prothrombin levels & thrombin formation.
57 Unexplained recurrent miscarriage In about half the women in the research studies, no cause could be found, so no specific treatment could be given.However, this group responded very well to a programme which removed as many stress factors as possible from their lives, resulting in an 80% success rate with the subsequent pregnancyPsychological support can improve outcome between the higher areas of the mind & the delicately balanced hormonal system
58 Women with unexplained recurrent miscarriage have an excellent prognosis for future pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit.After all these investigations 50% of recurrent aborters will have no abnormalities & these should be attributed to chromosomal defect in the conceptus.
59 ConclusionIn cases of adverse pregnancy outcomes APLA should be kept in mindDetailed history & tailor investigationsCouple should be counselled together .The only intervention to have demonstrated benefit is serial ultrasound scans in early months of pregnancy.Referral to a tertiary unit as multidisciplinary management is needed for patients with APLA / ThrombophilliaPsychological supportEducation & reassurance has an important role to play
60 Thromboprophylaxis for previous thromboembolic episode Risk categorypRisk factorsProphylaxisHigh riskTED (thromboembolicdisease)-Prev. TED-Prev TED+APLA-Prev TED+ family history of TED-Recurrent TED-TED in current preg.ANC:s/c UH orLMWHIntrapartum:s/c UHor LMWHPost partum:s/c UHor LMWH for 3-7 days f/b UH or LMWH or warfarin for 3-7 daysLow riskOne prev TED (No other risk factors)ANC: g oddIntrapartum or post partum:as above
61 Diagnosis of APLA can be challenging, due to fluctuating titers of the antibodies, a lack of agreement between laboratories concerning standardization of the assays, and debates among researchers and clinicians concerning which antibodies to measure. Although multiple APLAs might eventually be considered pathologic to pregnancies, anti-cardiolipin, anti-phosphotidylserine, and the 'lupus anticoagulant' are generally believed to be culprits when identified in women with pregnancy losses.
62 Rx APLA syndrome generally requires daily baby aspirin prior to conception & the use of baby aspirin & heparin as soon as pregnancy is diagnosedOne recently published study demonstrated an 80% success rate for treatment of APLA by this approach. The 20% failure rate is likely accounted for in large part by genetically-abnormal losses.More aggressive treatment of APLA occasionally involves the use of human intravenous immunoglobulin. This is an expensive therapy that has less clear-cut efficacy demonstrated. The use of empiric intravenous immunoglobulin should generally be discouraged, and is not endorsed by the American College of Obstetricans and Gynecologists.