Anticoagulation in Antiphospholipid Antibody Syndrome

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					    Anticoagulation in
Antiphospholipid Antibody
     Mark Kochenderfer
    Resident Grand Rounds
        March 5, 2002

• Patient is a 28 year old female with SLE
  diagnosed six years ago. Patient presented
  to general medicine last year with a
  thrombus in her subclavian vein. She had a
  history of a prior DVT and four
  miscarriages. Further testing revealed
  anticardiolipin antibodies.
• Antiphospholipid Antibodies recognize
  phospholipids and/or proteins associated
  with them.
• First recognition came in 1906 in
  conjunction with syphilis research
• First description of syndrome with
  thrombosis, recurrent miscarriage and
  thrombocytopenia by Hughes in 1983
• Advances in our understanding of the
  immune system has led to the discovery of
  antibodies that are associated with this
• Rapid advances in technology and basic
  science knowledge have outdistanced
  clinical studies causing some studies to be
  essentially worthless at completion because
  the knowledge behind them changed during
       Purpose of Presentation
• Review basic current understanding of
  pathogenesis and clinical features of APS

• Look at current issues in anticoagulation in

• Review data on anticoagulation in APS
 “Where we are at and where we
         are going”
• I. Introduction
• II. Pathogenesis
• A.theories on f(x)
• B.types of ab
• C.prevalance

• Antibodies are directed against
  phospholipids, plasma proteins bound to
  phospholipids, or unique antigens revealed
  during the interaction of the two.
• Mechanism of pathology poorly understood
• Some claim antibodies extraneous to APS
• Most plausible theory is antibodies interact
  with plasma proteins that bind to
  phospholipids. Many of these proteins are
  also anticoagulants in the clotting cascade
  like beta 2 glycoprotein 1 and prothrombin.
  Neutralization of these proteins disrupts
  physiologic anticoagulation.
            The Antibodies
• Lupus Anticoagulant (LA)

• Anticardiolipin Antibodies (aCL)

• anti Beta 2 glycoprotein antibodies
        Lupus Anticoagulant
• Now thought to react against prothrombin
• May result in elevated PTT
• Higher thrombotic potential than aCL when
  each are present alone
     Anticardiolipin Antibodies
• Used to be thought to react against
  cardiolipin but it is now thought to interact
  with B2GP1
• 85% of APS pts have both LA and aCL
           Anti Beta 2 GP1
• Discovered after LA and aCL
• Found without other two in 11% of APS pts
  and 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, and/or activation of platelets.
     Prevalence of Antibodies
• AB present in many conditions
• transient elevations common
• elevations common in autoimmune disease
  and infections ex. HIV, Hep C, syphilis
• 7% of 1014 admits to Gen Med at
  University Hospital had APA. Only 2%
  had APS
          Prevalence in Elderly
•   89 healthy females age 75-102
•   64% were aCL +
•   32% were anti B2GP1 +
•   differences in isotypes present or possibly
    reactivity towards B2GP1 may explain this
• IgG in mid to high titer most often
  associated with APS
• IgM not uncommon in APS
• IgA uncommon in APS except in African-
Clinical Features
• APS causes problems in multiple organ
• Basic pathologic change is thrombotic
  microangiopathy without perivascular
• APS is subdivided into primary and
  secondary APS
   Primary and Secondary APS
• Primary APS -APS in the absence of lupus
• Secondary APS-APS in pt with lupus
• Study compared pts with each and found
  only differences to be secondary had higher
  rate of hemolytic anemia, neutropenia, and
  low c4 levels
     Preliminary Criteria for
  Classification of definite APS
• Designed by International Symposium on
  Antiphospholipid Antibodies as to aid in
• Include clinical and laboratory crteria. Must
  have one of each for APS to be present.
            Clinical Criteria
• 1. Vascular Thrombosis: One or more
  clinical episodes of arterial, venous or small
  vessel thrombosis in any tissue or organ.
  Thrombosis must be confirmed by imaging
  or Doppler studies.
• 2. Pregnancy Morbidity
• a. one or more unexplained deaths of a
  morphologically normal fetus at or beyond
  10th week of gestation, with normal fetal
  morphology documented by ultrasound or
  direct exam of fetus OR
• b. one or more premature births of a
  morphologically normal fetus at or before
  the 34th week of gestation because of
• (continued) severe placental insuffiencey.
• c. Three or more unexplained consecutive
  spontaneous abortions before the 10th week
  of gestation, with maternal anatomic or
  hormonal abnormalities and paternal and
  maternal chromosomal causes excluded.
          Laboratory Criteria
• 1. Anticardiolipin antibody of IgG and/or
  IgM isotype in blood, present in medium or
  high titer, on two or more occasions, at least
  6 wks apart, measured by ELISA for
  B2GP1 dependent anticardiolipin
• 2. Lupus anticoagulant present in plasma,
  on 2 or more occasions at least 6 wks apart,
  detected according to the guidelines of the
  International Society on Thrombosis and
  Hemostatis in the following steps:
• a. Prolonged phospholipid-dependent
  coagulation demonstrated on a screening
  test eg aPTT,kaolin clotting time, dRvvt.
• B. Failure to correct the prolonged
  coagulation time on the screening test by
  mixing with normal platelet poor plasma.
• C. Shortening or correction of the prolonged
  coagulation time on the screening test by
  addition of excess phospholipid.
• D Exclusion of other coagulopathies eg.
  Factor VIII inhibitor
    Features Associated with APS

•   CLINICAL               • LABORATORY
•   Livedo reticularis     • low titer aCL
•   Cardiac valvulopathy
                           • IgA aCL
•   MS like syndrome
•   Seizures
                           • antiB2GP1 ab
•   Thrombocytopenia       • ab to prothrombin or
•   Hemolytic anemia         annexin
•   TIAs                   • False + test for
APS in Different Systems
• Both arterial and venous
• Two prospective studies found LA present
  in 8.5% and 14% of pts with first dvt
• another study pts with dvt and aCL were
  twice as likely to have subsequent dvts than
  those with dvt that are aCL negative
• Ischemic attacks most common, APA are
  present in 46% of pts with CVA under the
  age of 50.
• Increased seizure activity
• MS-like syndrome
• Livedo reticularis classic finding. Has
  mottled purple reticular fishnet pattern.
• Skin ulcerations also common
• 35-75% of pts with APS have valvular
• strong correlation between valvular
  disorders and CVAs
• role of APA in in CAD controversial
• Hypertension
• Thrombi in glomerulus
• Renal involvement more common than once
• 7-25% of women with recurrent
  miscarriages have APS as primary cause, in
  these women rate of untreated miscarriage
• Loss can occur throughout pregnancy, but
  what role APA have prior to 10 weeks
• Severe eclampsia and preeclampsia are also
• Even in treated populations preterm
  delivery rate 25%
• APA present in 5% of all pregnancies
  Testing for APA in Pregnancy
• 1. Severe preeclampsia before 34 wks
• 2. Unexplained stillbirth or fetal death after
  10 wks gestation
• 3. Severe intrauterine growth restriction
  prior to term
• 4. Abortions prior to 10 wks controversial.
  Most advocate screening after two 1st
  trimester losses with no other cause
• Present in 25% of patients
• Responds to steroids and other
  immunomodulating drugs
• Direct antibody interaction and platelet
  activation both play a role
         Hemolytic Anemia
• Rare complication
• antibody mediated
          Catastrophic APS
• Small % of APS pts develop failure of
  multiple organs in rapid succession
• mortality within 5 years 50%
Monitoring Warfarin Therapy in
    Basic Hematology Review
• Coumadin inhibits gamma carboxylation of
  coag factors II,VII,IX,X making inactive
  these vit K dependent factors and
  interrupting normal coagulation cascade.
• Coumadin also inhibits vit K dep Proteins C
  and S which are natural inhibitors of
    Basic Hematology Review
• Different commercial thromboplastins used
  in calculating PT and these vary in
  sensitivity to factors II, VII, X
  (thromboplastin is insensitive to to IX)
• To account for this INR created
• Calculated using international sensitivity
  index (ISI) for thromboplastin used
              Heme con’t
• ISI a correction factor for a particular
  thromboplastin used
• Of note, ISI and INR correct only for
  differences in sensitivities to vit K
  dependent coagulation factors
• INR invalid when coagulation problems
  occur in other proteins, eg liver disese
• Many reactions in cascade phospholipid dep
   Do APA interfere with INR?
• Ptt and dilute Russel viper venom time have
  been shown to have small elevations in APS
• Few studies mid 1990s implied Lupus
  Anticoagulant interference with PT resulted
  in high INR
• Tests were small and suffered form ISI
  calibration errors so a large multicenter
  study was undertaken to answer question
   Laboratory control of oral anticoagulant
treatment by the INR system in patients with
the antiphospholipid antibody syndrome and
             lupus anticoagulant.
     A. Tripodi, V. Chantarangkul et al.
       British Journal of Hematology
• 58 cases of APS on Coumadin and 57
  antibody negative patients on Coumadin
• Target INRs similar
• Samples collected frozen and shipped to
  coordinating center
• INRs calculated using nine most widely
  used thromboplastins which were calibrated
  at center and ISIs assigned
• 8/9 thromboplastins showed no statistical
• Thromborel R showed significant difference
  in INR between cases and controls as
  defined by percentage of patients with INR
  that was 20% greater than mean INR
• Factor X amidolytic activity and INR
  similar in cases and controls
Prophylaxis of patients with
Antiphospholipid Antibodies
• High incidence of thromboembolic events
  has led some to consider primary
  prophylaxis with aspirin or coumadin
• Difficult to study because of holes in our
  knowledge of APA
• To attempt to address question a decision
  analysis model was used
 Prophylactic Antithrombotic
  Therapy for Patients with
Systemic Lupus Erythematosus
       with or Without
 Antiphospholipid Antibodies
     D. Wahl, H. Bounameaux et al.
     Archives of Internal Medicine
• The following assumptions were made in
  the model
• 1. Daily ASA dose 100-325mg QD
• 2. INR targeted to 2-3
• 3. Only major hemorrhagic events
• 4. pts that suffered thrombotic event were
  still subject to future events.
•   Options in Analysis were:
•   1. observation
•   2. prophylactic aspirin
•   3. prophylactic warfarin
•   Outcomes were measured by tracking #
    thromboembolic events prevented and #
    bleeding events induced
• Aspirin group performed best in model. In
  this group 8 thrombotic events were
  prevented and only 1 hemorrhagic event
  induced per 100 patients over 5 year period.
• In Coumadin group it was estimated that
  10.2 thrombotic events were prevented and
  10.4 hemorrhagic events induced.

• Computer also calculated months of quality
  adjusted survival gain as part of Markov
  subtree model
• For the aspirin group survival gains varied
  between 14.7 months for a 20yo and 4.9
  monts for a 60 yo
• Study has obvious limitations of being
  computer simulation
• Risk of bleed with ASA was intentionally
• Not something to base practice decisions on
  but may lend some support to a practice
  many doctors elect to do anyway.
Anticoagulation in APS
• Use of oral Coumadin mainstay of therapy
• Until 1992 management outside of
  pregnancy unexplored
• We will look at the four major studies on
  this subject
 Antiphospholipid Thrombosis:
 Clinical Course after the First
Thrombotic Event in 70 Patients
     M. Rosove and M. Petronella
     Annals of Internal Medicine
•   Retrospective study
•   80% pts had primary APS 20% secondary
•   average age 45.3 SD 17.3
•   72% + aCL
•   64% + Lupus Anticoagulant
•   26% + false positive test result syphilis
• Outcomes were measured by observing site
  of initial and recurrent thrombotic events
  (venous or arterial) , kind of
  anticoagulation, and intensity of
• 1. Thrombotic events: 37pts (53%) had a
  total of 54 thrombotic events. In 23 patients
  with 1st event in venous circulation had 26
  of 31 recurrent events in the venous
  circulation. 14 pts with initial event in
  arterial circulation all 23 subsequent events
  were in the arterial system. 91% of
  recurrences were ipsilateral.
Anticoagulation and Thrombotic
• 1. No treatment group had 0.19 events
  peryear of followup
• 2. Aspirin alone group had .32 events per
  year which did not differ from no tx group
• 3. Warfarin group with INR<1.9 conferred
  no protection from thrombotic activity
• 4. Warfarin with target INR 2.0-2.9 had an
  event rate of 0.07 but did not reach
  significance (p=0.12)
• 5. INR > 3.0 group had no events (p<0.001)
• 6. Adding aspirin to Coumadin made no
  difference in outcomes.
 The Management of Thrombosis
in the Antiphospholipid Antibody
    M. Khamashta, M. Cuadrado et al.

• 147 pts with APS and h/o thrombosis were
  reviewed retrospectively.
• 62 primary APS, 66 secondary APS, 19
  APS with lupus like illness
• Median age 32
• 84% female
• 1. Ipsilateral vascular tree recurrence was
  again seen with 93% of patients with initial
  event in arterial circulation having
  subsequent events on arterial side and 76%
  of pts with initial event on venous side
  having subsequent events there.
• 1. No treatment group had .29 events per
  follow-up year
• 2. ASA was significantly different from no
  treatment group in initial analysis
  (p=0.013), however the no treatment group
  included a number of pregnant women so an
  analysis was done taking into account
  hypercoagulable states the difference
• 3. Patients on warfarin with a target INR of
  2.0-3.0 had .23 events per year of follow-up
  and did not differ significantly from the no
  treatment group in events. P=.27

• 4. Pts in warfarin group with target INR >
  3.0 had significantly fewer events. Rate
  was 0.015 events/ yr f-u (p<0.001)
• 5. Adding aspirin to warfarin made no
  difference from warfarin without asa
  targeted to same INR
• 6. It was noted in the data that there was a
  significant increase in the rate of thrombosis
  in the 6 months after warfarin cessation.
• 6. (cont) There were 21 events in 39 pts
  during this period. When compared with
  baseline rates of thrombosis difference is
  significant (p<0.001) This was also noted
  by Derksen in a smaller study.
 A Retrospective Review of 61
Patients With Antiphospholipid
   S.Krnic-Barrie, C. O’Connor et al.
     Archives of Internal Medicine
• 1. Retrospective Study
• 2. 61 patients were identified.
• 3. Outcomes measured were site of event,
  frequency of occurrence, and whether there
  was an elevation in events in the 6 months
  after cessation of warfarin.
• 4. Warfarin was not stratified by target INR
• 1. There was no difference between the
  aspirin and no treatment groups.
• 2. Only 51% of recurrences were ipsilateral
• 3. Warfarin group had significantly lower
  rate of thrombus over the no treatment
  group. (p=0.008)
• 4. There was no elevation in rate of events
  in six months after warfarin cessation.
Anticardiolipin Antibodies Predict Early
Recurrence of TE and Death among Pts
      with Venous TE following
        Anticoagulant Therapy

    S. Schulman, E. Svenungsson et al.
             American J Med
• Purpose of study to explore length of
  anticoagulation in APS
• prospective study. Pts with first event
  randomized to warfarin for 6 weeks or 6
  months while those with a second event
  randomized to 6 months of warfarin or
  indefinite therapy. Pts then tested for aCL.
• Target INR 2.0-2.85
• 412 in first event group and 211 in second
  event group
• study lasted four years
• only venous events were in study
• 1. 6 week group was not analyzed
  secondary to study dfficulties
• 2. Overall risk of death in aCL + pts was
  7% vs. 2.2% in non aCL group. (p=0.002)
• 3. Indefinite anticoagulation group there
  was one DVT in 19 pts over length of
  study.This person quit taking
  anticoagulation 2-8 months prior to event.
• In the group with their first recurrence
  anticoagulated for six months there was a
  significant difference between the aCL +
  and aCL negative groups in number of TE
  events over course of study (p=0.0013)
• Sharp rise in rate of TE was noted in the six
  months after cessationof warfarin
• 1 difficult to analyze
• 2 Raises question of lifetime
   Hemorrhagic Complications
• Rosove: 0.031 major events per year
• Khamashta: 0.017 major bleeding events
  per year
• These rates are similar to those for non APS
  patients anticoagulated to similar INRs
     APS refractory to warfarin
• No studies
• Possibilities include increasing target INR
  to 4.0, adding aspirin, or adding LMWH
Anticoagulation in Pregnancy
         with APS
Randomised controlled trial of
aspirin plus heparin in pregnant
       women with APS
       R. Rai, H. Cohen et al.
• 90 women with APS were randomized into
  two groups with one receiving 75mg of
  ASA and the other ASA and 5000u SQ
  heparin q12h
• outcomes measured were number of live
  births and number of miscarriages
• In the ASA group there were 19 live births
  and 26 miscarriages
• In the ASA+heparin group there were 32
  live births and 13 miscarriages
• Improvement in outcomes with heparin
  significant (p=0.01)
      General guidelines for
    anticoagulation of APS in
• SQ heparin 10,000u q12 or lovenox 1mg/kg
  sq qd
• Aspirin
• If miscarriage occurs with heparin and
  aspirin group and patient becomes pregnant
  again IVIG can be tried although RCT
  failed to show benefit
• Prednisone
        Future Possibilities
• PAPRE warfarin intensity
• PRECLUDE primary prevention
• 1. Although little data supporting use of
  aspirin for primary prevention I would still
  strongly consider it.
• 2. Pts with APS need anticoagulated to a
  target INR of 3.0
• 3. Measurement of INR is generally
  unaffected by APA although specific
  thromboplastins have been shown to be
• 4. In pregnancy use of ASA and heparin sq
  has been shown to reduce miscarriages.
• 5. Duration of anticoagulation therapy
  needed in APS patients not well
  characterized. A sharp increase with
  cessation of therapy has been noted for the
  first six months off Coumadin. Rate then
  seems to be linear. Long term
  anticoagulation should be strongly
• 6. It is difficult to practice EBM without
• 7. My typing skills have eroded since
• 8. It is difficult to work on grand rounds in
  the MIRC when Mohanty is on call.
          Back to the case...
• Pt has cont to have multisystem
  involvement causing frequent
  hospitalizations. She developed renal failure
  last summer and is now on dialysis. Pt is
  not compliant with anticoagulation while
  out of the hospital and pain
  medicationsgiven to treat pain from lupus
  have caused dependence problems. Pt also
  beginning to have problems from long term
• Use of steroids to control her lupus. She
  turns 29 next month.

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