Antiphospholipid antibody syndrome APS

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Antiphospholipid antibody syndrome (APS)

• KHABBAZ J. MD
• Homs military hospital
• 29/03/07

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APSEpidemiology

• 10-15 of thromboembolic disease are due to APS
• 1/3 of strokes occuring in younger peoples
  (without evident etiology) are due to APS

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APS

• Venous thrombosis are more common than arterial
  thrombosis
• The most common site of DVT is the calf
• The most common site of arterial thrombosis is
  the cerebral circulation
• The initial and long-term manifestations of the
  disease are similar in most, but not all the
  initial arterial thrombosis tends to be followed
  by an arterial event and the initial venous
  thrombosis by a venous event

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Venous thrombosis
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Thrombo-embolic disease
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Pulmonary embolism
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Cerebrovascular accidents
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Cardiovascular disease
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Libman-Sacks Vegetation
Cauliflower-like or flat, red multiple spreading
masses of 2 4 mm in diameter present on the
free margins or line of closure of the heart valve
Echo findings

• Prevalence
• TTE 10, TEE 30
• Mitral and aortic valves
• lt 1 cm2 in size
• Irregular borders
• Heterogenous echo density
• No independent motion
• Associated with thickening or regurgitation

(Cardiol Clin 199816531)
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Libman-Sacks Vegetation and MR
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Myocardial infarction
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Hematologic manifestations
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Cutaneous manifestations
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Other thrombosis
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Antiphospholipid Syndrome

• A clinicopathologic diagnosis

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Sapporo Criteria (Updated)

• International Consensus Statement on
  Classification Criteria for APS (2006).
• Clinical criteria.
• Vascular thrombosis.
• Pregnancy morbidity.
• Laboratory criteria.
• Lupus anticoagulant.
• Anticardiolipin IgG or IgM antibody.
• Anti-b2glycoprotein I IgG or IgM antibody.

-- Miyakis, et al., J.Thromb.Haemost., 2006 4
295-306.
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Clinical criteria for APS

• Vascular thrombosis.
• Venous thromboembolic disease (DVT, PE).
• Arterial thromboembolic disease.
• Small vessel thrombosis.
• Coexisting inherited or acquired thrombotic
  risk factors are not reasons for excluding
  patients from a diagnosis of APS trials.

-- Miyakis, et al., J.Thromb.Haemost., 2006 4
295-306.
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Laboratory criteria for APS

• Lupus anticoagulant defined by a functional,
  clot-based assay using the ISTH guidelines.
• Anticardiolipin IgG or IgM antibody.
• Anti-b2glycoprotein I IgG or IgM antibody.
• --Measured on 2 or more occasions at least 12
  weeks apart.

-- Miyakis, et al., J.Thromb.Haemost., 2006 4
295-306.
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Sapporo criteria

• a) Vascular Thrombosis in any organ or tissue or
  Pregnancy Event (one or more miscarriages after
  10th week of gestation, three or more
  miscarriages before 10th week of gestation, or
  one or more premature births before 34th week of
  gestation due to eclampsia) andb) Persistenly
  (12 weeks apart) Positive aPL (lupus
  anticoagulant test, moderate-to-high titer
  anticardiolipin antibodies, or moderate-to-high
  titer ß2-glycoprotein-I antibodies).

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Non-criteria APS findings

• Thrombocytopenia and/or hemolytic anemia.
• Transverse myelopathy or myelitis.
• Livido reticularis.
• Cardiac valve disease.
• Nephropathy.
• Non-thrombotic neurologic manifestations,
  including multiple sclerosis-like syndrome,
  chorea, or migraine headaches.

-- Miyakis, et al., J.Thromb.Haemost., 2006 4
295-306.
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APSTreatment
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What is the optimal antithrombotic therapy for a
patient with APS and thromboembolism?
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Target INR in patients with APS and venous
thrombosis

• Retrospective studies.
• Prospective studies investigating oral
  anticoagulant therapy that included patients
  subsequently found to have antiphospholipid
  antibodies.
• Prospective randomized clinical trials.

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ACCP Guidelines

• Treatment of venous thromboembolism in patients
  with antiphospholipid antibodies.
• We recommend a target INR of 2.5 (INR range,
  2.0 and 3.0) (Grade 1A). We recommend against
  high-intensity VKA therapy (Grade 1A).

-- Buller, et al., Chest, 2004 126 (Supplement)
401S.
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How long should patients with APS and venous
thrombosis be treated with warfarin?

• Schulman, et al., 1998.
• Prospective study.
• 412 patients with 1st episode of venous
  thrombo-embolism treated for 6 months with
  warfarin.
• 68 patients (17) with elevated antibody levels
  when warfarin therapy stopped.

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ACCP Guidelines

• Treatment of venous thromboembolism in patients
  with antiphospholipid antibodies.
• We recommend a target INR of 2.5 (INR range,
  2.0 and 3.0) (Grade 1A). We recommend against
  high-intensity VKA therapy (Grade 1A).
• We recommend treatment for 12 months (Grade 1C).
• We suggest indefinite anticoagulant therapy for
  these patients (Grade 2C).

-- Buller, et al., Chest, 2004 126 (Supplement)
401S.
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Is the INR accurate in all patients with APS?
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How do I treat venous thromboembolism in APS?

• Confirm baseline PT is normal.
• For an initial event, oral anticoagulation with a
  target INR of 2.5 for 12 months. Consider longer
  pending clinical course.
• Address additional prothrombotic risk factors.
• For recurrent events, consider more aggressive or
  alternative anticoagulation, or other strategy.

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Do any of the clinical laboratory tests identify
patients at risk for thromboembolic problems?
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Risk factors for recurrent vascular events
despite anticoagulation

• More than one prior thrombotic event
• TEE abnormalities
• aCL levels the risk of recurrence is twice as
  high among pts with aCL compared to those without
  such antibodies (2914)

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Anticardiolipin Antibodies and Recurrent Venous
Thromboembolism
-- Schulman, et al., Am J Med, 1998 104 332.
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What about patients with recurrent
thromboembolism despite therapeutic warfarin?
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Therapeutic options for recurrent thromboembolism
in APS

• Warfarin with a higher target INR (gt 3.0).
• Addition of an antiplatelet agent to warfarin.
• Change to an alternative anticoagulant (e.g., low
  molecular weight heparin).
• Immunomodulatory therapy.

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Recurrent Thrombosis in APS
Warfarin, INR 3.0
Warfarin, INR lt 3.0
ASA
None
-- Khamashta, et al., N Eng J Med, 1995 332 993.
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British Society of Haematology Guidelines

• For patients with APS and venous thrombosis,
  treatment for 6 months with a target INR of 2.5
  is reasonable.
• Recurrent venous thrombosis should be treated by
  long-term oral anticoagulation.
• Recurrence while the INR is between 2.0 and 3.0
  should lead to more intensive warfarin therapy,
  target INR 3.5, but this is uncommon.

-- Greaves, et al., Br.J.Haematol., 2000 109
704-15.
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What about patients with APS and arterial
thromboembolism?

• Retrospective studies suggest target INR gt 3.0.
• Rosove Brewer (1992).
• Khamashta, et al. (1995).
• Prospective randomized trials suggest target INR
  of 2 to 3.
• Crowther, et al. (2003).
• Finazzi, et al. (2005).

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British Society of Haematology Guidelines

• Because of the high risk of recurrence and
  likelihood of consequent permanent disability or
  death, stroke due to cerebral infarction in APS
  should be treated with long-term oral
  anticoagulant therapy, target INR 2.5 (optimal
  range 2.0-3.0) (level III evidence, grade B
  recommendation).

-- Greaves, et al., Br.J.Haematol., 2000 109
704-15.
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What about antiplatelet therapy alone in patients
with APS and stroke/TIA?
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ACCP Guidelines

• Prevention of noncardioembolic cerebral ischemic
  events.
• For most patients, we recommend antiplatelet
  agents over oral anticoagulation (Grade 1A).
• For patients with well-documented prothrombotic
  disorders, we suggest oral anticoagulation over
  antiplatelet agents (Grade 2C).

-- Albers, et al., Chest, 2004 126 (Supplement)
483S.
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Treatment of cardiac involvement
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Treatment of cardiac involvement

• Asymptomatic valve thickening low dose aspirin
  (81 mg/d)
• Embolic disease Heparin followed by warfarin
• MI Heparin followed by warfarin aspirin

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What options are there for prevention or
treatment of thromboembolism during pregnancy?
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ACCP Guidelines Pregnancy and aPL
-- Bates, et al., Chest, 2004 126 627S-644S.
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prevention or treatment of thromboembolism during
pregnancy

• During pregnancy, low molecular weight heparin is
  used instead of warfarin because of warfarin's
  teratogenicity.
• Women with recurrent miscarriage are often
  advised to take aspirin and to start low
  molecular weight heparin treatment after missing
  a period. This is the most effective treatment at
  the moment.

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What about the asymptomatic individual with an
antiphospholipid antibody?
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Recommendations for the asymptomatic individual
with aPL

• a low threshold for the use of
  thromboprophylaxis at times of high risk is
  indicated.
• Greaves, et al. Br.J.Haematol.,2000 109 704.
• In most instances there was consensus in adding
  low dose aspirin
• Alarcon-Segovia, et al. Lupus,2003 12 499.

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And what lies ahead?
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Future Directions

• Can we predict which patients with
  antiphospholipid antibodies will develop
  thromboembolic complications?
• Is there an inherited predisposition to
  developing antiphospholipid antibody syndrome?

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Familial Antiphospholipid Syndrome

• Family members of patients with APS have an
  increased incidence of autoimmune disorders.
• Genetics of APS is a clinical trial being
  developed by the Rare Thrombotic Diseases
  Clinical Research Consortium.
• For more information http//rarediseasesnetwork.
  epi.usf.edu/rtdc/

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Antiphospholipid Antibody Syndrome

• Venous or arterial thrombosis, recurrent fetal
  loss, or thrombocytopenia accompanied by an
  increased levels of antiphospholipid Ab (aPLs)
• Primary or secondary (SLE)
• Valvular lesions
• Vegetation, thickening, or regurgitation
• Prevalence
• 32 to 38 in primary APS
• A significantly higher prevalence of valvular
  defects in SLE pts with aPLs
• Therapy
• Long-term, high intensity oral
  anticoagulation (INR2.5-3)

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Thank you