SLE with Secondary APLA Complicating Pregnancy - PowerPoint Presentation

1. SLE with Secondary APLA Complicating PregnancyPresentor Dr. B.SreevidyaFNB Resident, Fernandez HospitalOn 09.05.2022

2. 27 year old Mrs.A, SSC , NCMG4 A3, 12 + 6 weeks of gestation k/c/o SLE with secondary APS Missed miscarriage

3. Medical HistoryRecurrent deep venous thrombosis-left UL and LLNot investigated Started on heparin-Stopped Heparin on her

4. 2015: Swelling of left lower limb associated with gangrenous ulcer on the leg Left lower limb arterial thrombosis with secondary ulcerationEvaluationANA 4+, ds DNA +, LAC +ve, aCl + ve Anti Ro/La –ve 2D ECHO revealed mild PAH, RVSP 40 mm Hg

5. Started on Heparin with ACITROM overlap along with WYSOLONE, HCQ, SILDENAFILDeveloped secondary infection of the ulcer, non responsive to antibiotics, underwent debridement followed by skin grafting

6. 2017 July:C/O SOB – class 2 x 1 month2D ECHO: mild TR, mild PAH , RVSP 45 mm HgAs the lady was desirous of pregnancy, planned for cardiac catheterization:- Pulmonary artery pressure was normal

7. Surgical H/O: H/O skin graftingFamily H/O: Diabetes in fatherAllergic/personal H/O: nil significant

8. Obstetric H/OPregYearGA at fetal loss1201822.6 w2210917 w3202011.1 w4202112.4 w

9. Obstetric H/O2017: November1st pregnancy: Spontaneous conception Scan at 7.6 wks- twin gestation with missed miscarriage of twin 2Ds DNAPositiveC3 levelsLowHematologicalThrombocytopenia (1 L)SGOT/PT72/94 (transaminitis)SLEDAI4

10. 1st Pregnancy MaternalWas on WYSOLONE, HCQ, LMWH 40 mg, LDA 75 mgOn f/u, platelet count normalized, SGPT- 50 (dec trend)Was changed to WARFARIN after 14 weeks in v/o financial reasonsFetalNT- normalTIFFA/ Fetal echo- normal, mech PR interval – normalScan at 22 w 6d revealed IUFD ( FL- 33.2 mm < 5th c)

11. 1st Pregnancy Admitted for IPMERPC, warfarin was stopped, as INR was high , she received Inj.Vit K 10 mg IV, 6 FFPBirthed a stillborn , macerated male baby weighing 360 gDeclined autopsy and placental HPEPost abortion- UFH with warfarin overlap

12. June 2018 (Interpregnancy period)Revisited rheumatologistc/o occasional right sided pleuritic painWas on WYSOLONE, HCQ, WARFARINDs DNA1.3 ( positive)C3/C469 ( low) /27 ( Normal)In v/o serologically active SLE, was advised to postpone conceptionSGOT/PT were normalAnti ds DNA: >1.1 +veC3: 90-180C4:10-40

13. 2nd Pregnancy Feb 2019:2nd pregnancy : Spontaneous conception, unplannedWARFARIN was changed to CLEXANE 60 mg OD s/c (dose increased from 40 mg of prev preg)Ds DNA3PositiveC3/C476/22C3 lowAnti Ro/La0.8/0.8negative

14. 2nd Pregnancy MaternalTransaminitis ( SGOT/SGPT: 78/178)MGE: Tab.URSOCOL 300 mg twice daily f/u with monthly SGOT/SGPTWas on WYSOLONE, HCQ, LMWH 60 mg, LDA 75 mgFetalNT normal, Efts-screen positive for Preeclampsia ( 1: 10)Scan at 17 weeks- IUFD, FL- 19.2 mm ( < 5th c), e/o subcutaneous edema +IPMERPC doneBirthed male baby, weighing 60 gPlacental HPE: Features s/o decidual arteriopathy, most probably a/w APS

15. G2- G3 Interval PeriodSGOT/SGPT fluctuatingMGE consultationUSG abdomen- mild raised echotexture of the liverASMA, anti LKM ab :–ve Serum igg raised : 2370( 700-1600 N)Liver biopsy- macrovesicular steatosis ? steroid inducedKept on oral omega 3 FA + vit ESteroid dosage was reduced and AZATHIOPRINE 50 mg was added as steroid sparing agent

16. 3rd Pregnancy-April 2020 MaternalWas on AZR, Wysolone, HCQ, ECOSPRIN, AcitromAcitrom stopped and CLEXANE started at 60 mg/day doseanemic, Hb: 8.2 g%FetalMissed miscarriage at 11.1 wks, CRL 15 mmReceived, IPMERPCRPOC : 2.8* 2 cm +IPMERPC doneBirthed male baby, weighing 60 gPlacental HPE: Features s/o decidual arteriopathy, most probably a/w APS

17. DateHbTLCPlatelets7/7/202028001 L8/7/2020220050k10/7/20207.9320026kUFH was stopped in v/o thrombocytopeniaAZR stopped in v/o leucopeniaWysolone dose increased to 50 mg/dayAs platelet count started to improve, acitrom restarted with heparin overlap and heparin stopped laterWysolone tapered to 10 mg/day

18. Persistent leucopenia D/D AZR induced vs disease flare Serological evidence of disease activity ( ds DNA- 2.9, low C3 and C4, anemia +, diffuse non scarring alopecia)AZR dose increased to 75 mg and advised against conception2 months F/U- parameters normalized

19. G4 (Present Pregnancy)December 2021: spontaneous , unplanned pregnancyConceived while on rx for migraneAcitrom stopped, started on CLEXANE 100 mg /day ( dose increased from prev pregs 40  60  100 mg) after confirmation of viabilityAt conception, ds DNA borderline +ve, C3 slightly low, LFT normalHad missed miscarriage at 12.4 wks, CRL- 42.5 mm

20. 4th PregnancyMother was admitted for the inpatient medical management of missed miscarriageO/E: Mild pallorPR:90 bpm, BP: 120/88 mm Hg, H/L:NAD, P/A softClexane changed to UFH, dose withheld after starting MISOPROSTOLHad IPMERPCPost abortion , Plt count- 58,000, thromboprophylaxis- withheld, Wysolone dose increased to 10 mg

21. Final DiagnosisA4, k/c/o SLE with mild active disease, secondary APS, thrombotic and obstetric morbidity (refractory)

22. Antiphospholipid Antibody Syndrome (APS)A/k/a hughes syndrome ( 1983)Autoimmune disorderTypes of APSPeer reviewed chapter- Klara et al, DOI: 10.5772/intecopen.72509

23. Pathophysiology Apl are heterogenous group of antibodies which bind withReview article:Rheumatol Clin, 2017; 13(11):30-36

24. Include:

25. B 2 Glycoprotein 1

26. PathophysiologyPathogenetic mechanisms of antiphospholipid antibody production in antiphospholipid syndrome. World J Rheumatol 2015; 5(2): 59-68Willis R, Gonzalez EB. Pathogenetic mechanisms of antiphospholipid antibody production in antiphospholipid syndrome. World J Rheumatol 2015; 5(2): 59-68 [DOI: 10.5499/wjr.v5.i2.59]

27. Pathogenesis of Thrombosis

28. Pathogenesis of Obstetric Morbidity

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31. Obstetric APS- PathophysiologyHypocomplimentemia is found in ½ of pts with obs APS

32. Epidemiology of APSaPL are seen in 1-5 % of normal healthy populationSeen in 15-30 % of individuals with SLEFamilial occurrence has been reported25% of women with RPL, 1/3rd of stroke pts < 50 years are diagnosed with APS15-20 % of pts with APS develop DVT/ or strokePrevalence increases with ageJ Prenat Med 2011 April-June 5(2):41-53,, ASCLS 2017, 30( 1) 7-14;

33. Imp infectious triggersViral (HIV, EBV, CMV, adenovirus)Bacterial ( IE, TB, mycoplasma pneumonia)Spirochetal ( syphilis, leptospirosis, Lymes disease)Parasitic (malaria)

34. Clinical manifestations of APS

35. Arterial thrombosisCVA, extremity gangrene, mesenteric infarction, aortic occlusionVenous thrombosisDVT, Pul embolism, mesenteric, hepatic, renal vein thrombosis, adrenal insufficiencyObstetric complicationsPreembryonic and embryonic losses, early and late fetal loss, preterm delivery d/t placental insufficiencyCutaneousLivido reticularis, cutaneous necrosis, pyoderma like ulceration, digital gangreneNeurologicalChorea, transverse myelitis, MS like syndrome, headaches, memory loss, epilepsy, blurred vision , dizzinessRenalNephropathy with glomerular thrombosis, cortical necrosis, renal infarctionHematologicalAutoimmune hemolytic anemia, immune thrombocytopeniaCardiacMitral/ or aortic insufficiency, intracardiac thrombus, coronary artery thrombosisAvascular necrosis of femoral headCatastrophic APSMODS (Thrombosis of >/= 2 organs)

36. Diagnosis of APS

37. Diagnosis of APS2006- Sydney, Australia1999- Sappor0, Japan

38. Classification Criteria

39. Sydney Criteria- 2006Abnormal/ non reassuring fetal surveillance testsAbnormal DopplersOligohydramniosPostnatal birth weight < 10 c for GA

40.

41. Points to be notedThrombosis must be confirmed by objective validated criteria- imaging/histopathologyFor histopathological confirmation, thrombosis must be present without significant evidence of inflammationIn case of fetal death, normal morphology must be established by ultrasound or direct examination of the fetus

42. Points to be notedClassification of APS should be avoided if < 12 weeks or > 5 years separate the positive aPL test and the clinical manifestationCoexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trialsSuperficial venous thrombosis is not included in the clinical criteria

43. Testing for aPL Antibodies

44. LACLAC- 1st described by Conley and Hartmann in 1952- in 2 SLE pts who presented with bleeding diathesis- lupus+ anticoagulantGroup of heterogenous autoantibodies ( IgM/IgG) Bind to negatively charged phospholipids or their binding proteins such as, B2GP1, prothrombin etcParadox, since majority of pts with LAC experience thrombosis rather than bleeding

45. Mechanisms of Coagulation

46. Understanding the Pathophysiology of LACPhospholipid surfaces are required for coagulation to occurWhen coagulation complexes are form on these surfaces, thrombin is generated and leads to fibrin formationWhen LACs are present in the plasma , they prevent these coagulation complexes from attaching to the PL surface in the invitro cogulation assays ( where a limited amount of PL is present in the reagent)As a result of the limited amount of the PL in the reagent , PL dependent clot based assays such as the APTT are prolonged

47. APTT reagents

48. Hence LAC lead to prolongation of APTT (low PL content reagent) in invitro studiesHowever, such prolongation does not occur invivo Reason: There is an unlimited source of PL on the surface of platelets and erythrocytes in the circulation and on the endotheliumPositive LAC testing has a high specificity for APS

49. Different Types of LAC assaysDilute Russel Viper venom time (dRVVT)Silica Clotting Time (SCT)Hexagonal phase phospholipid neutralization (STACLOT-LA)Kaolin clotting time (KCT)Dilute Prothrombin Time (dPT)Platelet neutralization procedure

50. Dilute Russell Viper Venom Time (Drvvt)

51. dRVVTPrinciple: activation of factor X at the beginning of the common pathway by an enzyme derived from the Russel Viper venom( Daboia russella)Sensitive to B2GP1 antibodiesCorrelates very strongly with thrombosis

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53. dRVVT screen ratio = dRVVT screen result/confirm result > 1.2 Presence of LAC

54.

55. Preanalytical variables that can affect the test

56. ISTH/SSC recommends the dRVVT as the 1st line of screening test followed by LAC sensitive APTT ( low PL conc) LAC should be considered positive if one of the two tests gives a positive resultThe use of >2 assays increases the false positive rate

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58.

59. aPL profileThe aPL profile is an important factor in determining the risk of thrombosis and obstetric events Triple positivity is associated with high risk of complicationsLA positivity a/w thrombosisB2GP1 positivity a/w obstetric complications

60. PREGNANTS studyMulticentre, retrospective cohort study750 pregnant women with primary APLA on LDA + Prophylactic heparin

61. Obstetric Complications

62. Live birth rate

63. Despite standard treatment with LDA and heparin the live birth rate in triple-positive APLA was only 30 %

64. Preconceptional Counselling

65. What the, to be , mother needs to know?Complications of APS in pregnancyMaternalFetalThrombosisHypertensive disorders of pregnancy ( early onset, severe)HIT, heparin induced osteoporosisCAPSMiscarriageFetal deathPrematurity ( spontaneous/iatrogenic)Growth restriction ComplicationNo RxRxThrombosis/stroke in preg 5 %v.lessPreclampsia30 %15 %FGR305-15 %

66. The various anticoagulation prophylaxis regimens, risks and limitationsAbout the risks of HIT, heparin induced osteoporosis and recommendations for appropriate protective measuresEducate the woman about the S/S of thrombosis With appropriate treatment the likelihood of a successful pregnancy is in excess of 70 %

67. Antenatal managementEarly bookingStart Heparin, once viability is established and continue until late in pregnancyPlatelet count monitoringCalcium supplementations , weight bearing exercises ( those on heparin)Those on long term anticoagulation with WARFARIN, change over to Heparin before 6 weeks of pregnancy

68. Overview of Anticoagulation during PregnancyLDA + Heparin throughout pregPP- Heparin for 6 weeks

69. Obstetric APS treated with prophylactic heparin during pregnancy, continue for 6 weeks PP

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72. Heparin In APS without Thrombosis- What do the International Bodies Say?APS- Recurrent RPL2/4 trials- no benefit of adding LMWH over AspirinAspirin alone- live birth rate- 70 %Cochrane review and ACCP- Aspirin + heparinACOG- surveillance vs heparin (LDA + heparin should be considered)APS- Late preg morbidityNo well designed trials

73. Antenatal Management cont..Multidisciplinary careScreen for preeclampsia at every visitPrenatal visits every 2-4 weeks until 20-24 weeks and every 1-2 weeks thereafterFetal growth monitoring Antenatal fetal surveillance from 30-32 weeks onwards ( earlier in case of uteroplacental insufficiency)

74. Planned deliveryAvoid post datesLSCS for obstetric indicationChange over from LMWH to UFH before deliveryLDA to be stopped after 36 weeks- not a contraindication for neuraxial anesthesia Mother to be told to with hold heparin in case of symptoms suggestive of labour

75. Labour and DeliveryProphylactic LMWH should be discontinued at least 12 hours prior to scheduled induction/cesarean section, or as soon as the mother sets into labor, 24 hours for therapeutic LMWHSubcutaneous UFH dosed twice daily with a total dose < 10,000 units/day is not a contraindication to neuraxial anesthesiaDaily dose > 10000 u/day or more than twice-daily dosing of UFH, wait for 4-6 hours before giving regional anesthesia

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77. Continuous EFHR monitoring during labour ( d/t inc risk of uteroplacental insufficiency)

78. Postnatal ManagementAnticoagulation to be resumed 4-6 hours after vaginal delivery, 12 hours after c sectionWarfarin may be substituted for heparinAnticogulation to be continued for 6 weeks after delivery in women with no prev h/o thrombosis and longer for those with h/o thrombosisA recent meta-analysis found that low dose aspirin daily in women with APS based on obstetric factors alone may decrease the risk of an initial thrombotic event

79. Pharmacology of Heparin

80. All these agents are effective only against fluid based clotting factors (not against bound clotting factors, c/f- DTI)

81.

82. However, UFH is still needed in the following situations

83. Why does UFH require Monitoring and How is it Done?UFH is a heterogenous mixture of different length strands of heparin It sticks to endothelial cells, macrophages and various heparin binding proteinsThis makes the pharmacology unpredictable, requiring monitoring

84. Monitoring- How and Rationale

85. Low Molecular Weight HeparinSeveral formulations are available:Enoxaparin : greatestexperience Dalteparin Nadroparin Advantages and disadvantages over UFHAdvantagesDisadvantagesEasy dosingCostLess risk of HIT, osteoporosisRisk of accumulation in renal failureMore predictable kineticsMonitoring requires non routine test (anti Xa levels)More reliable A/CresponseIncomplete reversal by Protamine sulphate

86. Doesn’t generally require monitoringIndications for monitoring while on EnoxaparinBorderline renal functionUnusual weight (< 50 kg/ > 150 kg)PregnancyUnexpected bleedingBefore emergency procedure

87. How to monitor while on LMWH?By anti Xa levels , measured 4 hours after administering the dose ( corrsp to peak blood levels)Target anti Xa levels for various indictaions

88. Dosing of Enoxaparin

89.

90. FondaparinuxMOA: inhibits only Xa via ATcan be used in cases of HITC/I in renal failureE/O safety in pregnancy as per recent studies

91. HIT

92. Heparin Induced ThrombocytopeniaImmune mediated adverse drug reactionOften, unrecognised and undiagnosedTwo typesType 1- non immune, occurs within 48-72 hrs of intiation, mild TCP, no inc risk of thrombosisType 2- immune mediated

93. Seen in 1-5 % receiving UFHTCP- moderate severity ( 50-80k)Absolute (<1.5 L/cu.mm) or relative ( > 50 % drop compared to preheaprin value)Fall in platelets starts 5-14 d after initiation of heparinDespite TCP, strongly a/w thrombosis

94. Diagnosis: Mainly clinical, supported by lab testingCriteria for the diagnosis of HITNormal platelet count before commencement of heparinThrombocytopenia(TCP): > 50% fall from baselineOnset within 5-10 days after heparin inititaionAcute thrombotic eventExclusion of other causes of TCPResolution of TCP after cessation of heparinHIT Ab seroconversion

95. Screening for HITObstetric pts receiving prophylactic dose UFH or LMWH after first receiving UFHPost op pts receiving LMWHBaseline platelet count, monitor PLT count every 2-3 days from day 4 to day 14 or until UFH is topped whichever is earlier (when practical)Non postop pts receiving LMWHNo monitoring requiredAs recommended by College of American Pathologists. Adapted with permission from Warkentin TE, Greinacher A. Heparin‐induced thrombocytopenia: recognition, treatment, and prevention. Chest 2004;126:311S–37S.

96. Treatment of HIT- General principlesStop all forms of heparinSend blood samples for lab confirmationInitiate alternative anticoagulation( Fondaparinux, Danaparoid), cont for 2-3 monthsMonitor for thrombotic eventDonot start warfarin until platelet count improvesAvoid prophylactic blood transfusions

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98. Oral Anticoagulants

99.

100. WarfarinVit K antagonistInhibits synthesis of CF- 2,7,9,10 and protein C and S ( endogenous anticoagulants)The anticoagulant effect of Warfarin is dependent on the clearance of functional clotting factors from the circulationTherefore, the antithrombotic effect of warfarin is not evident until 5th day of therapy (time taken for the clearance of prothrombin)No role of loading dose of warfarin (>/= 7.5 mg/day)  inc risk of bleeding and paradoxical thrombosis d/t inh of prot C

101. What to do if Rapid Anticoagulation is required?Initial dose of Heparin should be used and overlapped with Warfarin for approximately 4- 5 daysINR should be monitored ideally every day ( or atleast every A/D), until INR is in the therapeutic range for atleast 2 consecutive days, then heparin can be discontinued .Therapeutic INR: 2-3 ( except for prosthetic valves- 2.5-3.5)

102. Reasons for Unexpected Fluctuations in INRChange in dietPoor complianceUndisclosed drug useAlcohol consumption Self-medicationLab errors

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104. Journal of Applied Hematology - Volume 10, Issue 4, October-December 2019

105. Direct Oral AnticoagulantsAdvantages over warfarinQuick onset of actionPredictable pharmacokineticsMinimal drug and food interactionsDo not require frequent monitoring and dosage adjustmentsRapid reversal possible (specific antidotes +)Bind to bound C/F as well, prevent clot propogation Not approved for use in preganancyRecent guidelines have recommended DOACS as the first line anticoagulants for the management of provoked proximal DVT and non valvular AFClinicians are more likely to encounter them in practsie, therefore knowledge about DOACS is important

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107. 614 cases of DOAC exposure in pregnancyMedian duration of exposure: 5.3 wks of GA6% fetal abnormality noted, 4 %- major birth defects potentially related to DOAC exposureHowever, ISTH recommends against elective termination of pregnancy for the fear of embryotoxicity, but suggests close pregnancy surveillance

108. Refractory OAPS20-30 % of cases are refractory to the standard careDrugMOAEvidenceHCQInhibits aPL displacement of annexin 5 on syncytiotrophoblastsAnti TNF Complement inhibition3 ongoing RCTsHYPATIAHIBISCUSHYDROSALPCortocosteroidsDiverse pathwaysBramham et alIVIGNeutralise autoantibodiesDecrease NK cell activityMetaanalysis by Ruffatti et allTNF alpha- targeted therapiesInhibit T cell mediated tissue damageIMPACT study-improve pregnancy in APS with certolizumab therapy

109. Recommended Steps in the Treatment of Refractory OAPSStep 1LDA started 4 weeks before conception.Prophylactic heparin from the time of conceptionStep 2Step 1 + HCQ 200- 400 mg/day, acc to body weightStep 3Step 2 + low dose prednisolone 10-15 mg/d ( started as soon as pregnancy is known ) or increasing LWMH doseStep 4Step 3+ add IVIGs and / or perform plasma exchangeStep 5Step 4 +add anti TNF (infliximab, etanercept, but better to use adalimumab or certrolizumab)Step 6Consider adding hydrophilic statins (pravastatin 20-40 mg/day), or eculizumabRef:Lupus.210;22:6-17.

110. Take home messagesPreconceptional LDA, benefits early stages of implantationLA a/w thrombosis, BAGP1 a/w obst morbidity Triple positive APLA- low live birth rateStopAspirin- 36 weeksUFH- 6 HProphylactic LMWH- 12 HTherapeutic LMWH – 24 HPrior to considering neuraxial anesthesia

111. All cases of APS receiving antenatal heparin, continue for 6 weeks post partumMonitoringUFH- APTT ( not useful in LAC positive pts)LMWH- anti XaWarfarin- PT/INR

112. Thank You