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

-

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.