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Anticardiolipin Antibodies

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					Antiphospholipid Syndrome
             Prof. Dr. Suchitra N. Pandit
             MD, DNBE, DFP, FRCOG, FICOG, B.Pharm
      Consultant Obstetrician & Gynaecologist
     Kokilaben Dhirubhai Hospital, Mumbai ,India
   Clinical secretary –MOGS, Vice President - FOGSI (2008-09)
Chairperson -Young Talent promotion committee FOGSI (2003-07)
        Antiphospholipid ( APLA ) syndrome
 Antiphospholipid syndrome (Hughes syndrome) is a
  disorder of immune system ,characterised by excessive
  clotting of blood ,thrombocytopenia & /or adverse
  pregnancy outcomes
 Body recognizes negatively charged phospholipids on
  cell membrane as foreign & produces antibodies
  against them leading to an acquired autoimmune
  thrombophilia
 Patients have laboratory evidence for antibodies ( IgG,
  IgM or IgA ) against phospholipids or phospholipid-
  binding protein cofactors in their blood
How many types of APLA syndromes are there

 A.) One

 B.) two

 C.) Three

 D.) Four
   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 I
 In catastrophic APLA (rare ), APS leads to rapid organ failure
  due to generalised thrombosis & a high risk of death
 Other rare antibodies to phosphotidyl ethanolamine &
  phosphotidylserine are also associated with it
   Thrombophilic defects
either acquired or inherited
Thrombophilia - tendency to thrombosis
                          Lupus anticoagulant
  Acquired
   APLA                     antibodies
                      Anticardiolipin antibodies

 Myeloprolipherative diseases
 Malignancy
 Paroxysmal nocturnal Haemoglobinuria
 Nephrotic syndrome
                  Inherited
 Hyperhomocysteinemia (C677T) mutation
 Factor V Leiden mutation (A506G) mutation
 Mutation in prothrombin ( G 20210 A)
 Prothrombin II (PTII) mutation
 Protein S deficiency
 Protein C deficiency
All these conditions should be investigated
for APLA except :
A.) Early onset severe preeclampsia
B.) Arterial or venous thrombosis
C.) Unexplained fetal growth restriction
D.) Gestational Diabetes
    Primary antiphospholipid antibody syndrome
Presentation may be totally asymptomatic or in a classical manner :
 Various clinical presentations :
 Recurrent pregnancy loss
 Unexplained second or third trimester loss
 Early onset severe preeclampsia
 Arterial or venous thrombosis
 Unexplained fetal growth restriction
 Prolonged coagulation studies
 Autoimmune diseases
 Cardiac valvular diseases
 Neurological disorders
 Thrombocytopenia
              Diagnosis of APLA
 Challenging !!!
 Due to fluctuating titers of the antibodies,
 Lack of agreement between laboratories concerning
  standardization of the assays
 Debates among researchers & clinicians concerning
  which antibodies to measure.
   Which is not an APLA antibody ?

A.) Anti Ro

B.) Lupus Anticoagulant (LAC)

C.) Anticardiolipin Antibodies (ACL)

D.) Anti insulin antibodies
      Which are the Antibodies
   Lupus Anticoagulant (LAC)

 Anticardiolipin Antibodies (ACL)

 Anti Beta 2 glycoprotein antibodies

 Other antibodies
             Lupus anticoagulant ( LAC)
 LAC is characterized by a prolonged partial thromboplastin
  time & paradoxically the so-called ‘anticoagulant’ is a
  powerful thrombotic agent in vivo
 Higher thrombotic potential than ACL when present alone
 LAC interferes with platelet function, causing aggregation &
  thrombosis & also interferes with endothelial function,
  causing procoagulant activation & thrombosis
 Prevalence of LAC in low risk population is < 1%
  Bad obstetric history - 9.1%
  Early pre eclampsia - 16%,
  Abruption - 33%
  Systemic lupus erythematosus - 34%
 Patient typically has a prolonged APTT that does not
  correct in 80:20 mixture with normal human plasma

 Prolonged Dilute Russel viper venom time (DRVVT),
  Kaolin clotting test (KCT),(TDT/DTT) or prothombin time

 Due 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.
       Lupus anticoagulant (LAC)
  Prolongation of which of these tests is most
  sensitive for LAC ?
A.)   Activated partial thromboplastin

B.)   Dilute Russel Viper venom

C.)   Kaolin clotting time

D.)   Partial Thrombin time
        Anticardiolipin Antibodies
 Were thought to react against cardiolipin but it is
  now thought to interact with B2GP1
 85% of APS pts have both LA & aCL
 These 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
           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.
             Sapporo criteria
International Consensus Conference held in
 Sapporo (’98)
Clinical criteria of ( APAS )
Thrombosis, one or more confirmed episodes
of venous, arterial, or small vessels disease
‘ Coexisting inherited or acquired thrombotic
 risk factors are not reasons for excluding
 patients from a diagnosis of APS trials.’
             Sapporo Criteria (updated)
     Pregnancy criteria :
   One or more unexplained fetal deaths > 10 wks of pregnancy
   One or more preeclampsia / eclampsia or placental
    insufficiencies occurring before 34 weeks .
   Three or more unexplained consecutive spontaneous
    abortions < 10 weeks
    Laboratory criteria
   LAC defined by a functional, clot-based assay (ISTH
    guidelines)
   ACL (IgG or IgM) antibody
   Anti-b2 glycoprotein I ,IgG or IgM antibody
                Miyakis, et al., J. Thromb. Haemost.,2006; 4: 295-306.
        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 tissue

 Lab. confirmation of presence of aPL

 Some 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 negative

 Transient elevations common. Elevations common in autoimmune
  disease & infections ex. HIV, Hep C, syphilis
 Principal pathogenic mechanisms mediated by APL
Interference with

                                       Protein C/S pathway
a.) Soluble coagulation
                                            inhibition;
    factors
                                      fibrinolysis inhibition
                              Induction of a pro-adhesive, pro-
                                inflammatory & pro-coagulant
b.) Coagulation cells:             endothelial phenotype ;
                          induction of a procoagulant phenotype in
                                          monocytes
Interference with :

                          Reduction of proliferation & differentiation;
a.) Trophoblast cells:
                            Gonadotrophin secretion impairment
  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%)
             Causes of pregnancy loss

      Chromosomal              Environmental

55% of occult & early losses
                                           hormonal
5% of recurrent losses.
                                      anatomical

                               Immunological
                               45% of early losses
                               95% of late losses
                   Aneuploidy
Aneuploid fetus risk in women
> 35yr. age
                                            1/80


Inherent risk of fetal loss after
amniocentesis                              1/200


 Standard of care is to offer genetic amniocentesis
      for all pregnant women older than 35 years
What is Recurrent pregnancy loss ?

What actually causes it ?
                 Definition
 A recurrent pregnancy loss (RPL) is 3 or more
 consecutive, spontaneous pregnancy losses, under
 20 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
   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 APLA
 APL 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 ; 337:1630-1631, 1997
Pregnancy loss in autoimmune connective tissue
               disorders (CTDs)
 Adverse outcomes like IUGR, prematurity, recurrent
  pregnancy loss & stillbirth are common
 Systemic lupus erythematosus (SLE) is prototype , others
  are rheumatoid arthritis, scleroderma, Behcet’s disease &
  Sjogren’s syndrome
 Recent 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
         How do you proceed ?
 Interview the couple together
 History of the case is very important
 Clinical examination
 Investigations as per the history
 Reassurance & counselling
 Treatment plan : Drugs, maternal & fetal
  surveillance , dealing with complications
 Timely referral to a tertiary centre
             Special Investigations
 LAC tested by prolonged coagulation time (inhibition of
  phospholipids)
 APTT , KCT , TTIT
 Most accurate - Dilute russel viper venom test (DRVVT)
 ACL - ELISA - IgG (GPL) IgM (MPL)
 IgG/ IgM isotypes of anticardiolipin & antiphosphotidyl
   serine antibodies
 In c/o low titres-repeat after 6-8wks (can revert to normal)
 Transient low titres can be found in viral fever
 If autoimmune disorders are suspected ANA, anti –nDNA,
  antiSm, anti-Ro/SSA antibody, anti La (SSP)
  So how does one manage the drug
      treatment in pregnancy ?
General guidelines for anticoagulation in
Pregnancy with APS leading to recurrent
            pregnancy loss

       Very controversial issue !
       Commonly used Drugs
• Steroids : Reduces ACA, normalises prolongation of
             invitro coagulation
• Complications : ? perinatal outcome
                       preterm labour,
                        preeclampsia
• Low dose Aspirin (LDA) : Selective inhibition of
                             Thromboxane A2
                             No effect on PGI2
• Azathioprine
• Warfarin
Which is the commonly used drug for APLA ?

A.) Progesterone
B.) Folic acid
C.) Low dose Aspirin
D.) RU- 486
       Unfractionated Heparin (UFH)
 Potentiates complex formation with
  AT III + factor VII A  XII A & thrombin
 Complications : Reduces platelet bleeding &
                       B.M.D.
   Low molecular weight Heparin (LMWH)
 Once daily dose, less monitoring
 Lesser osteopenia, does not cross placenta
 Cost factor !!
                 Trials
 Heparin vs Aspirin + prednisolone
  Live birth 75%
  Pre-eclampsia, preterm delivery more in latter
  group
 L.S. + LDA Vs Heparin + LDA (n=20)
 No placebo
 Large multicentric trials needed
                             Cowchock et al .1994
  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 hourly
 Outcomes measured were number of live births &
  miscarriages
 LDA group had 19 live births & 26 miscarriages
 LDA + heparin group had 32 live births & 13 miscarriages
 Significant (p=0.01) improvement in outcomes with heparin
                                R. Rai, H.Cohen et al..,BMJ. (1997 )
       Antiphospolipid antibodies
 Presence of Antiphosholipid antibodies may cause
 recurrent pregnancy loss

 Are antibodies directly responsible ?

 Should all women with APA be treated ?

 How do you treat a women with positive APLA ?
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
 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 between 3.0 - 4.0.
 Patients 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
 Since APLA reacts with phospholipids both aPTT & PT can
  be affected. If UFH used to anticoagulate patients with APLA
  monitor heparin levels ( 0.35 - 0.70 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 (0.7 - 1.0 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
       ACCP Guidelines : Pregnancy & APL

      Manifestation                  Recommendation                   Grade

Antiphospholipid antibody;   Surveillance, or mini-dose heparin, or    2C
no prior VTE or pregnancy    prophylactic LMWH, & /or aspirin
loss



Antiphospholipid antibody;   Adjusted dose UFH or LMWH, plus           1C
prior thrombotic event       low-dose aspirin.




                                - Bates, et al., Chest, 2004; 126: 627S - 644S
Can pregnancy outcome be improved ?
       Management of pregnant women
 Surveillance depends on past obstetric history
 LDA preconception & LDA + LMWH has 80% success
  rate for treatment of APLA ( Feinberg et al,’ 97 ).
 Refer preferably to a tertiary centre with a neonatal backup
 Team effort including an obstetrician , hematologist,
  physician, & neonatologist
 Vigilant monitoring
 B.P, platelets, complement levels , renal function test (to
  asses target organ damage )
                Care of the fetus
 Surveillance depends on past obstetric history

 1st trim U.S.G : viability & dating , nuchal & nasal bone

 U.S.G at 19 weeks & serial scans with doppler for early
  diagnosis of IUGR & waveform abnormalites

 Inj Betamethasone 2 doses for enhancing lung maturity

 Timely delivery in a centre with a good neonatal backup
      Future Possibilities

 PAPRE warfarin intensity

 PRECLUDE primary prevention

 More frequent use of LMWH, IVIG
  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 thrombosis
 The current recommendation would be to do very careful
  search for thrombosis. Brain MRI in patients with SLE & in
  patients with any neurological symptom
 If this work-up is negative follow the patient very closely
   Does 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
 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 2.0 - 3.0
  Venous Thrombosis: Warfarin to an INR of 3.0 - 3.5. Patients
  who "break through" warfarin should receive heparin.
Inherited Thrombophilia
            Inherited Thrombophilia
 Three important inherited thrombophilias :
• Mutation in factor V Leiden causing resistance to
 activated protein C (responsible of 20–30% of venous
 thromboembolism events.)
• Mutation in prothrombin (guanine 20210 adenine )
• Mutation in methylene tetrahydrofolate reductase
 (MTHFR) (cytosine 677 thymine (C677T) ) This
 is responsible for reduced MTHFR activity & is most
 frequent cause of mild hyperhomocysteinemia &
 is found in 5–15% of the population.
     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
                Protein S deficiency
 Protein 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.
        MTHFR (C677T) mutation

 A 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.
         MTHFR (C677T) mutation

 Responsible 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
  thrombosis
  Dietary restriction of folate & vitamin B12 remains
  the most common cause.
    Prothrombin (G20210A) mutation

 A change of G to A at position 20210 in
  prothrombin (prothrombin 20210A) elevates
  baseline prothrombin levels & thrombin
  formation.
    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 pregnancy
 Psychological support can improve outcome between
  the higher areas of the mind & the delicately balanced
  hormonal system
 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.
                      Conclusion
 In cases of adverse pregnancy outcomes APLA should be
  kept in mind
 Detailed history & tailor investigations
 Couple 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 / Thrombophillia
 Psychological support
 Education & reassurance has an important role to play
            Thromboprophylaxis for previous
                thromboembolic episode
Risk categoryp        Risk factors                Prophylaxis


High risk             -Prev. TED                   ANC:s/c UH or
                      -Prev TED+APLA               LMWH
TED (thromboembolic   -Prev TED+ family history    Intrapartum:s/c UH
     disease)         of TED                        or LMWH
                      -Recurrent TED              Post partum:s/c UH
                      -TED in current preg.       or LMWH for 3-7 days f/b
                                                  UH or LMWH or warfarin
                                                  for 3-7 days
Low risk              One prev TED (No other      ANC: g odd
                      risk factors)               Intrapartum or post
                                                  partum:as above
 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.
 Rx APLA syndrome generally requires daily baby aspirin prior
  to conception & the use of baby aspirin & heparin as soon as
  pregnancy is diagnosed
 One 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.