Anti phospholipid syndrome
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Transcript of Anti phospholipid syndrome
Anti Phospho-Lipid Antibody (APLA) Syndrome (APS)
Other namesMultiple terms for APS exist. Some confusing.
•Hughes syndrome
•Anticardiolipin Syndrome (ACL)
•Anti- Phospho Lipid Antibody (APLA) syndrome
Other namesMultiple terms for APS exist. Some confusing.
• Lupus anticoagulant (LA) syndrome: Misleading term because – patients with APS may not have SLE, and – LA is associated with thrombotic rather than
hemorrhagic complications.
Other namesMultiple terms for APS exist. Some confusing.
• Lupus anticoagulant (LA) syndrome: Misleading term because – Patients with APS may not have SLE, and – LA is associated with thrombotic rather than
hemorrhagic complications.
Anti-phospholipid syndrome (APS)Is a disorder that manifests as- • Recurrent venous or arterial thrombosis and/or
• Complications of pregnancy (fetal losses) +
• Characteristic lab abnormalities.
Anti-phospholipid syndrome (APS)APS is currently the preferred term.
Previous Classification-• Primary - no associated disease, • Secondary- in association with SLE /other
rheumatic (AI) disorders
Current classification - 1. APS with, or 2. APS without associated rheumatic disease.
Anti-phospholipid syndrome (APS)APS is currently the preferred term.
Previous Classification-• Primary - no associated disease, • Secondary- in association with SLE /other
rheumatic (AI) disorders
Current classification - 1. APS with, or 2. APS without associated rheumatic disease.
Antiphospholipid syndrome (APS)
Although antiphospholipid (aPL) abs are linked to APS, their role in pathogenesis (cause or an epiphenomenon) is unclear.
Up to 5% of healthy people have aPL abs.
APS• It is a heterogenous disorder in terms of
clinical manifestations and range of autoantibodies.
• In 2006, revised criteria for the diagnosis of APS were published in an international consensus statement.
• At least one clinical criterion and one laboratory criterion must be present for a patient to be classified as having APS.
Antiphospholipid Syndrome Criteria Sydney revision of Sapporo criteria 2006
CLINICAL CRITERIA
1. Vascular Thrombosis
2. Pregnancy Morbidity: a) death of normal fetus
at > 10 wks b) premature birth at < 34
wks due to preeclampsia c) >3 consecutive abortions at <10wks d) placental insufficiency at < 34 wks
LAB CRITERA
1. anti-Cardiolipin IgG / IgM
2. anti–beta-2 glycoprotein I (GP1)
3. Lupus anticoagulant (LAC)
- medium to - high titer - at least X 2 times - 12 wks apart
Antiphospholipid Syndrome Criteria Sydney revision of Sapporo criteria 2006
CLINICAL CRITERIA
1. Vascular Thrombosis
2. Pregnancy Morbidity: a) death of normal fetus
at > 10 wks b) premature birth at < 34
wks due to preeclampsia c) >3 consecutive abortions at <10wks d) placental insufficiency at < 34 wks
LAB CRITERA
1. anti-Cardiolipin IgG / IgM
2. anti–beta-2 glycoprotein I (GP1)
3. Lupus anticoagulant (LAC)
- medium to - high titer - at least X 2 times - 12 wks apartDefinite APS: 1 Clinical + 1 Lab criteria
APS: The clinical criteria are-1. Vascular thrombosis –One or more clinical episodes of arterial,
venous, or small-vessel thrombosis – In any tissue or organ – Thrombosis may involve (cerebral, coronary,
pulmonary, limb, hepatic, renal, ocular or adrenal) any circulation. –Confirmed by imaging, doppler, or histopath
studies
APS: The clinical criteria are-1. Vascular thrombosis
Inv is warranted if DVT/ PE/ acute ischemia/ MI/ CVA (esp. recurrent) is present
in a young individual in the absence of other risk factors.
The clinical criteria are-2. Pregnancy morbidity –One or more late-term (>10 wks) spontaneous
abortions–One or more premature births of a
morphologically healthy neonate at /before 34 wks due to pre/eclampsia or severe placental insufficiency – Three or more unexplained, consecutive,
spontaneous abortions before 10 wks gestation
Laboratory criteria:Patients must have raised1. IgG or IgM anticardiolipin (aCL), or 2. anti–beta-2 glycoprotein I (GP1), or 3. Lupus anticoagulant (LA)
On • at least 2 occasions • at least 12 weeks apart
Additionally..• Other antiphospholipid (aPL)–associated clinical
features recognized by the 2006 consensus statement but not included in the criteria are-
• Cardiac valve disease • Livedo reticularis • Thrombocytopenia • Nephropathy, and • Neurologic manifestations
Suspect APLA syndrome if…
• Thrombosis• Miscarriage• Heart murmur or cardiac valvular vegetations• Hematologic abnormalities (TCP or HA)• Nephropathy• Non-thrombotic neurologic symptoms • Unexplained adrenal insufficiency• Avascular necrosis of bone• Pulmonary hypertension
Suspect APLA syndrome if…
• Thrombosis• Miscarriage• heart murmur or cardiac valvular vegetations• hematologic abnormalities (TCP or HA)• nephropathy• Non-thrombotic neurologic symptoms, • Unexplained adrenal insufficiency• Avascular necrosis of bone• Pulmonary hypertension - in the absence of other risk factors
APLA Syndrome - Etiology
APS is an autoimmune disorder of unknown cause.
Possible triggers are- • Associated autoimmune or rheumatic diseases • Infections and • Drugs associated with the LA or aCL antibodies.
APLA Syndrome -EtiologyAsso diseases Infections Drugs Others
SLE Syphilis Cardiac- Procainamide, quinidine, propranolol, hydralazine
Familial association
Sjogrens HCV Neuroleptic /psychiatric - Phenytoin, chlorpromazine
HLA associations: between aCL ab and indivs with certain HLA genes
RA HIV Other - Interferon alfa, quinine, amoxicillinAI TCP HTLV I
AI HA MalariaPsoriatic arthropathy
Bacterial septicemia
PSSMCTDPMR/ GCABehcet’s
Differential Diagnosis
• DIC• IE• TTP
• Acquired prothrombotic disorders
Acquired prothrombotic disorders
• Conditions associated with a hypercoagulable state: - Pregnancy and postpartum - major surgery - Obesity and immobility - malignancy - Congestive heart failure - Nephrotic syndrome
• Estrogen treatment
• Antiphospholipid syndrome
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APS: Laboratory Studies
The hallmark that defines antiphospholipid syndrome (APS) is
• The presence of antiphospholipid (APL) antibodies or
• Abnormalities in phospholipid-dependent tests of coagulation.
APS: Laboratory Studies
The hallmark that defines antiphospholipid syndrome (APS) is
• The presence of antiphospholipid (APL) antibodies or
• Abnormalities in phospholipid-dependent tests of coagulation.
APS: Laboratory Studies
The hallmark that defines antiphospholipid syndrome (APS) is
• The presence of antiphospholipid (APL) antibodies or
• Abnormalities in phospholipid-dependent tests of coagulation.
APS: Laboratory Studies
• In addition to the clinical criteria listed, at least one of the following laboratory criteria is necessary for the classification of APS:
APS: Laboratory Studies• Presence of LA in plasma on 2 or more occasions
at least 12 weeks apart
• Presence of moderate to high levels of anticardiolipin (aCL) (IgG or IgM) in serum/ plasma (ie, >40 IgG phospholipid units (GPL)/mL or IgM phospholipid units (MPL)/mL or >99th percentile) on 2 or more occasions at least 12 weeks apart
APS: Laboratory Studies• Presence of moderate to high levels of anti–beta-2 glycoprotein I antibodies (IgG or
IgM) in serum or plasma (>99th percentile) on 2 or more occasions at least 12 weeks apart
• Presence of LA in plasma on 2 or more occasions at least 12 weeks apart
APS: Laboratory StudiesLA is directed against plasma coagulation molecules.• Results in the paradoxical prolongation of clotting assays,
such as aPTT, kaolin clotting time, and dilute Russell viper venom time (DRVVT).
• The presence of LA is confirmed by mixing normal aCL antibodies react primarily to membrane phospholipids• platelet-poor plasma with the patient's plasma.• If a clotting factor is deficient, the addition of normal
plasma corrects the prolonged clotting time. • If the clotting time does not normalize during mixing
studies, an inhibitor is present; the absence of a specific clotting factor inhibitor confirms that a LA is present.
APS: Laboratory StudiesLA is directed against plasma coagulation
molecules.• Results in the paradoxical prolongation of clotting
assays, (such as aPTT, kaolin clotting time, and dilute Russell viper venom time (DRVVT)).
APS: Laboratory StudiesLA is directed against plasma coagulation
molecules.• Results in the paradoxical prolongation of clotting
assays, such as aPTT, kaolin clotting time, and dilute Russell viper venom time (DRVVT).
• The presence of LA is confirmed by mixing normal platelet-poor plasma with the patient's plasma.
If
APS: Laboratory Studies• If a clotting factor is deficient, the addition of
normal platelet poor plasma corrects the prolonged clotting time.
• If the clotting time does not normalize during mixing studies, an inhibitor is present; the absence of a specific clotting factor inhibitor confirms that a LA is present.
APS: Laboratory Studies
• aCL antibodies react primarily to membrane phospholipids
APS: Summary of Laboratory StudiesFollowing laboratory tests should be done:• aCL antibodies (IgG, IgM)• Anti–beta-2 glycoprotein I antibodies (IgG, IgM)• Activated partial thromboplastin time (aPTT)• LA tests such as DRVVT• Serologic test for syphilis (false-positive result)• CBC count (thrombocytopenia, hemolytic
anemia) • A low ANA level may be present and does not
necessarily imply coexisting SLE.
False Positives• Infections:
- Syphilis, TB, Q-fever, Spotted Fever, Klebsiella, HCV,
Leprosy, HIV. - The abs are usually transient, not b2 GPI
dependent
• Malignancy: Lymphoma, paraproteinemia
• Drug induced: phenothiazines, procainamide, quinidine,
phenytoin, hydralazine
APS Treatment: Thrombosis• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.• Based on the most recent evidence, a reasonable
target for the INR is –Venous thrombosis -2.0-3.0–Arterial thrombosis 3.0– Recurrent thrombotic events -may require 3.0-4.0 – Severe or refractory cases- combination of warfarin+
aspirin maybe used. • Treatment is generally lifelong.
APS Treatment: Thrombosis• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.• Based on the most recent evidence, a reasonable
target for the INR is – Venous thrombosis -2.0-3.0– Arterial thrombosis 3.0– Recurrent thrombotic events -may require 3.0-4.0
• Severe or refractory cases- combination of warfarin+ aspirin maybe used.
• Treatment is generally lifelong.
APS Treatment: Thrombosis• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.• Based on the most recent evidence, a reasonable
target for the INR is – Venous thrombosis -2.0-3.0– Arterial thrombosis 3.0– Recurrent thrombotic events -may require 3.0-4.0
• Severe or refractory cases- combination of warfarin+ aspirin maybe used.
• Treatment is generally lifelong.
APS Treatment: Thrombosis• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.• Based on the most recent evidence, a reasonable
target for the INR is –Venous thrombosis -2.0-3.0–Arterial thrombosis 3.0– Recurrent thrombotic events -may require 3.0-4.0
• Severe or refractory cases- combination of warfarin+ aspirin maybe used.
• Treatment is generally lifelong.
APS Treatment: Obstetric considerations Guidelines available- • Heparin safe in pregnancy, preferred LMWH. • Warfarin contraindicated in pregnancy. • Heparin and warfarin safe in breast feeding.• No history of thrombosis -Prophylaxis• History of thrombosis -Full anticoagulation
APS Treatment: Obstetric considerations Guidelines available- • History of thrombosis -Full anticoagulation– Prophylactic SC heparin (LMWH) + low-dose
aspirin during pregnancy. – Rx withheld at delivery. Restarted after, continued
for 6-12 wks postpartum. – Long-term anticoagulation then continued
postpartum.
APS Treatment: Obstetric considerations Guidelines available- • History of thrombosis -Full anticoagulation
• Corticosteroids -not been proven effective. Increase maternal morbidity and fetal prematurity rates.
Prophylactic therapy• Eliminate other risk factors, such as oral
contraceptives, smoking, hypertension, or hyperlipidemia.
• Low-dose aspirin; the effectiveness as primary prevention for APS remains unproven.
• Clopidogrel anecdotal reports (aspirin allergy). • In SLE, consider hydroxychloroquine, for intrinsic
antithrombotic properties.• Statins, esp for hyperlipidemia.
Catastrophic Antiphospholipid Syndrome (CAPS)
• Catastrophic antiphospholipid syndrome is rare, affecting < 1% of those with antiphospholipid syndrome.
• Also called Asherson's syndrome after the researcher who described it in 1990s.
• These patients are generally very ill, often with active SLE.
• There is widespread thrombosis in several vascular beds
Catastrophic Antiphospholipid Syndrome (CAPS)
Treatment • Intensive anticoagulation • Plasma exchange • Corticosteroids appears beneficial No controlled trials have been performed. • IV Ig -some benefit• Cyclophosphamide in selected cases (SLE-
associated CAPS).
Take Home Messages: Anti- Phospholipid Syndrome
• Due to the wide spectrum of manifestations any clinician may encounter patients with APS
• This is a potentially treatable condition
• The best treatment, at present to prevent recurrent thrombosis is anticoagulation.
• The optimal duration and intensity is controversial.
THM: Venous or Arterial thrombosis
1. Initial treatment with Heparin
2. Start Warfarin
3. Stop Heparin when therapeutic INR achieved
Current Recommendations• Asymptomatic aPL no treatment (Aspirin?)• Venous thrombosis Warfarin INR 2.0-3.0• Arterial thrombosis Warfarin INR 3.0• Recurrent thrombosis Warfarin INR 3.0-4.0 + Aspirin
• CAPS Anticoagulation + CS + IVIg or plasmapheresis
Potentially usable
• Non-aspirin antiplatelet agents• Hydroxychloroquine• Statins
• Thrombin inhibitors• Rituximab• Recombinant activated protein C• Prostaglandin and prostacyclin• Anti-cytokine
Thrombocytopenia
• Mild to moderate- Platelets > 50,000: No treatment
• Severe- <50,000: corticosteroids
• Corticosteroid resistant cases: HCQ IVIG, Immunosuppressive drugs, Splenectomy
Current Recommendations
Pregnancy Fetal protection• Asymptomatic aPL no treatment• Single loss <10wks no treatment• Recurrent loss* <10wks prophylactic heparin +ASA up to 6-12 wks postpartum, ASA
after(?)
• Recurrent loss < 10 wks therapeutic heparin + ASA, + thrombosis warfarin postpartum
• Prior thrombosis therapeutic heparin + ASA warfarin postpartum
* Late fetal loss IUGR severe pre-eclampsia
Other Rx for APL Ass pregnancy loss• Corticosteroids : - associated with significant maternal and
fetal morbidity - ineffective
• Immunosuppression: azathioprine, plasmapheresis: numbers treated too small for conclusion
• IVIG: may be salvage therapy in women who fail on Heparin + Aspirin
Take Home Messages: Anti- Phospholipid Syndrome
• Due to the wide spectrum of manifestations any clinician may encounter patients with APS
• This is a potentially treatable condition
• The best treatment, at present to prevent recurrent thrombosis is anticoagulation.
• The optimal duration and intensity is controversial.