Isfahan

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ANTIPHOSPHOLIPID
SYNDROME

Yousef mohammadikebar
Fellowship of Rheumatology
Shariati hospital

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DEFINITION
• Antiphospholipid Antibody Syndrome (APS)

− An autoimmune disease

 Vascular Thrombosis
 Pregnancy Morbidity
 Antiphospholipid antibody in plasma

Levine, NEJM 2002

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Antiphospholipid Syndrome

• Primary:
an isolated condition

• Secondary:
secondary to SLE or other connective
tissue diseases

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 HISTORY Isfahan
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1900 2000

5
De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906-wasserman
diagnostic assay to
Detect syphilis

1900 2000

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De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906 Diagnostic assay to

detect syphilis

1900 2000

1941 - pangborn
Cardiolipin is major antigen
for reagin in syphilis assay

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De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906 Diagnostic assay to 1952 –conley& hartman

detect syphilis Discovery of LA

1952 biological false-positive

syphilis assay

1900 2000

1941 Cardiolipin : Major Ag

in syphilis assay

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De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906 Diagnostic assay to 1952 An inhibitor that prolonged

detect syphilis coagulation time in vitro

1952 biological false-positive

syphilis assay

1900 2000

1941 Cardiolipin : Major Ag

in syphilis assay

1954 First report of the correlation

between prolonged clotting
in vitro and pregnancy morbidity
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De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906 Diagnostic assay to 1952 An inhibitor that prolonged

detect syphilis coagulation time in vitro

1952 biological false-positive

syphilis assay

1900 2000

1963 –Bowie
1941 Cardiolipin : Major Ag
Apl paradox
in syphilis assay
prolonged CT and thrombosis
1954 First report of the correlation
between prolonged clotting
in vitro and pregnancy morbidity
10
De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906 Diagnostic assay to 1952 An inhibitor that prolonged 1983 -The first aPL-Ab
detect syphilis coagulation time in vitro anticardiolipin
ELISA
1952 biological false-positive
syphilis assay

1900 2000

1963 First report of the

1941 Cardiolipin : Major Ag
antiphospholipid paradox
in syphilis assay

1954 First report of the correlation

between prolonged clotting
in vitro and pregnancy morbidity
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De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906 Diagnostic assay to 1952 An inhibitor that prolonged 1983 the first
detect syphilis coagulation time in vitro anticardiolipin
ELISA
1952 biological false-positive
syphilis assay

1900 2000

1963 First report of the

1941 Cardiolipin : Major Ag
antiphospholipid paradox
in syphilis assay

1954 First report of the correlation 1990 Anti β2 GP I

between prolonged clotting
in vitro and pregnancy morbidity
12
De laat, Nature Rheumatology 2008
 HISTORY Isfahan
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1906 Diagnostic assay to 1952 An inhibitor that prolonged 1983 the first
detect syphilis coagulation time in vitro anticardiolipin
ELISA
1952 biological false-positive
syphilis assay

1900 2000

1963 First report of the

1941 Cardiolipin : Major Ag
antiphospholipid paradox
in syphilis assay

1954 First report of the correlation 1990 Anti β2

between prolonged clotting Glycoprotein I
in vitro and pregnancy morbidity
13
1991 Prothrombin
 HISTORY Isfahan
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1999 Sapporo criteria

1906 Diagnostic assay to 1952 An inhibitor that prolonged 1983 the first
detect syphilis coagulation time in vitro anticardiolipin
ELISA
1952 biological false-positive
syphilis assay

1900 2000

1963 First report of the

1941 Cardiolipin : Major Ag
antiphospholipid paradox
in syphilis assay

1954 First report of the correlation 1990 Anti β2

between prolonged clotting Glycoprotein I
in vitro and pregnancy morbidity
14
1991 Prothrombin
 HISTORY Isfahan
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1999 Sapporo criteria

1906 Diagnostic assay to 1952 An inhibitor that prolonged 1983 the first
detect syphilis coagulation time in vitro anticardiolipin
ELISA
1952 biological false-positive
syphilis assay

1900 2000

1963 First report of the

1941 Cardiolipin : Major Ag
antiphospholipid paradox
in syphilis assay

1954 First report of the correlation 1990 Anti β2

between prolonged clotting Glycoprotein I 2006
in vitro and pregnancy morbidity New
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1991 Prothrombin Criteria
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EPIDEMIOLOGY

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EPIDEMIOLOGY
• Primary APS, the cause of:

− 15- 20% of DVT

− 1/ 3 of stroke < 50

− 10-15% of fetal loss

Ginsburg, Ann Intern Med, 1992

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EPIDEMIOLOGY
• aPL antibody

− General population 1% - 5%

− SLE 20% - 40%

− RA 20%
Salmon, Nature Rheumatology, 2007

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EPIDEMIOLOGY
• 60-80% of primary APS : female

• 0.5% to 2% of normal pregnant women, have

aPLs.

• prevalence of aPL-positive ELISA tests

increases with age

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EPIDEMIOLOGY
• aPL antibody

− History of thrombosis 30 % - 40%

Love , Ann Intern Med, 1990

− Stroke < 50 y 4% - 46%
Hart, Stroke, 1984
Brey, Neurology, 1990
Nncini, Stroke, 1992
Petri, J.Autoimmun, 2000

− MI 5%-15%
Vaarala, 1998, Lupus

− Recurrent fetal loss 10% - 19%

Khamashta, Hughes Syndrome, 2006 20
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EPIDEMIOLOGY

• APS & SLE

• 31% of SLE : LA+

• 23-47% of SLE : ACL+
• 20% of SLE : Anti beta2GP1+

• 50% of LA + : SLE
• 45% of APS : ANA+ ,Anti-dsDNA+
• 8% of primary APS : SLE

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CLASSIFICATION CRITERIA

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2006 CLASSIFICATION REVISED 1391

CRITERIA
• 1 Clinical Criteria • 1 Laboratory Criteria

Miyaki , J thromb.Heamostat, 2006

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2006 CLASSIFICATION REVISED 1391

CRITERIA
• 1 Clinical Criteria • 1 Laboratory Criteria

− Vascular Thrombosis

Or

− Pregnancy Morbidity

Miyaki , J thromb.Heamostat, 2006

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2006 CLASSIFICATION REVISED 1391

CRITERIA
• 1 Clinical Criteria • 1 Laboratory Criteria

− Vascular Thrombosis − Lupus Anticoagulant

Or
Or − Anti Cardiolipin antibody
(IgG and/or IgM)
Or
− Pregnancy Morbidity
− Anti β2 GPI antibody
(IgG and/or IgM)

Miyaki , J thromb.Heamostat, 2006

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2006 CLASSIFICATION REVISED 1391

CRITERIA
• Vascular Thrombosis

− ≥ 1 episodes of arterial, venous or small venous thrombosis

− Confirmation with imaging or pathology

− Thrombosis without inflammation

Miyaki , J thromb.Heamostat, 2006

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2006 CLASSIFICATION REVISED 1391

CRITERIA
• Pregnancy Morbidity

− ≥ 3 abortions , < 10th weeks of gestation (R/O other causes)

− ≥ 1 death , ≥ 10th weeks of gestation (R/O other causes)

− ≥ 1 premature birth, < 34th weeks of gestation due to

 Ecclampsia
 Severe precclampsia
 Placental insufficiency
Miyaki , J thromb.Heamostat, 2006
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PROBABLE APS
• Not Clinical Criteria • Not Laboratory Criteria

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PROBABLE APS
• Not Clinical Criteria • Not Laboratory Criteria

− Livedo Reticularis
− Valvular Heart Disease
− Nephropathy
− Thrombocytopenia
− Neurological manifestations

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PROBABLE APS
• Not Clinical Criteria • Not Laboratory Criteria

− Livedo Reticularis − IgA anticardiolipin

− Valvular Heart Disease − Anti prothrombin Ab
− Nephropathy − Anti phosphatydilserine Ab
− Thrombocytopenia
− Neurological manifestations

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LABORATORY EVALUATION
• Anti Cardiolipin Ab
− ElISA (IgM-IgG)
− Sensitive
− Not specific
− IgG correlates with clinical manifestations
Gharavi, Ann Rheum Dis,1987

• Anti β2 glycoprotein I
− ElISA (IgM-IgG)
− More specific

• Lupus anticoagulant
− A functional assay 31
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LUPUS ANTICOAGULANT TEST
Screening
Procedure

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J Thromb Haemost 2009
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LUPUS ANTICOAGULANT TEST
Screening Testing for dRVVT and APTT
Procedure

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J Thromb Haemost 2009
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LUPUS ANTICOAGULANT TEST
Screening Testing for dRVVT and APTT
Procedure

Mixing
Procedure

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J Thromb Haemost 2009
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LUPUS ANTICOAGULANT TEST
Screening Testing for dRVVT and APTT
Procedure

Mixing Mixing 1:1 patient: PNP

Procedure And repeat testing

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J Thromb Haemost 2009
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LUPUS ANTICOAGULANT TEST
Screening Testing for dRVVT and APTT
Procedure

Mixing Mixing 1:1 patient: PNP

Procedure And repeat testing

Confirmation
Procedure

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J Thromb Haemost 2009
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LUPUS ANTICOAGULANT TEST
Screening Testing for dRVVT and APTT
Procedure

Mixing Mixing 1:1 patient: PNP

Procedure And repeat testing

Confirmation Repeat testing with

Procedure excess PL

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J Thromb Haemost 2009
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LUPUS ANTICOAGULANT TEST
Screening Testing for dRVVT and APTT
Procedure

Mixing Mixing 1:1 patient: PNP

Procedure And repeat testing

Confirmation Repeat testing with

Procedure excess PL

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LA is Confirmed J Thromb Haemost 2009
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PATHOGENESIS

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Pathogenic clotting mechanism

mediated by aPL

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Meroni,nature of rheumatology ,2011

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(1) aPL interact with endothelial cells, primarily through binding

of β2GPI on the cell surface, and induce a procoagulant and
proinflammatory endothelial phenotype.
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Meroni,nature of rheumatology ,2011
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2) aPL upregulate tissue factor expression on endothelial cells and

blood monocytes, and promote endothelial leukocyte adhesion,
cytokine secretion and PGE2 synthesis.
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Meroni,nature of rheumatology ,2011
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(3) aPL recognize phospholipid-binding proteins expressed on

platelets—aPL binding potentiates platelet aggregation .

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Meroni,nature of rheumatology ,2011
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(4) aPL interfere with plasma components of the coagulation

cascade, by inhibiting anticoagulant activity, by displacing the
binding of the natural anticoagulant annexin A5 to anionic
structures.
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Meroni,nature of rheumatology ,2011
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These mechanisms all is necessary but not sufficient for clotting.

Clot formation seems to require a 'second hit‘.
Complement activation seems to be necessary for clot formation in vivo. 

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Meroni,nature of rheumatology ,2011
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SCENARIO

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First hit: 1391
aPL

Khamashta , Hughes Syndrome, 2006

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First hit: 1391
HLA aPL
Infections
Vaccination
….?

Khamashta , Hughes Syndrome, 2006

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 Isfahan
First hit: 1391
HLA aPL
Infections
Vaccination
….?

Antiβ2GPI

Khamashta , Hughes Syndrome, 2006

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 Isfahan
First hit: 1391
HLA aPL
Infections
Vaccination
….?

Antiβ2GPI

Vessel
wall

Khamashta , Hughes Syndrome, 2006

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First hit: 1391
HLA aPL
Infections
Vaccination
….? Immobilization
Antiβ2GPI Pregnancy Second
hit
Hyperlipidemia

Smoking

Vessel
wall

Khamashta , Hughes Syndrome, 2006

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First hit: 1391
aPL

Second
hit

Vessel
wall
Khamashta , Hughes Syndrome, 2006
Meroni, Nature Rheumatology, 2011
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First hit: 1391
aPL

THROMBOSIS Second
hit

Vessel
wall
Khamashta , Hughes Syndrome, 2006
Meroni, Nature Rheumatology, 2011
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Meroni, Nature Rheumatology, 2011 Isfahan
Main Effects of aPL on Placenta 1391

Umbilical Cord Fetal Blodd

Vessels
Intravillous space

Mtaernal Blood vessels

Blood Vessels Decidua Trophoblast
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Meroni, Nature Rheumatology, 2011 Isfahan
Main Effects of aPL on Placenta 1391

Umbilical Cord Fetal Blodd

Vessels
Intravillous space

Mtaernal Blood vessels

Blood Vessels Decidua Trophoblast
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aPL induced placental thrombosis
Monocyte, Platelet, endothelial cell activation
Meroni, Nature Rheumatology, 2011 Isfahan
Main Effects of aPL on Placenta 1391

Umbilical Cord Fetal Blodd

Vessels
Intravillous space

Mtaernal Blood vessels

Blood Vessels Decidua Trophoblast
57
Anti-β2GPI antibodies react with trophoblasts
aPL induced placental thrombosis
Inhibition of proliferation, differentiation;
Monocyte, Platelet, endothelial cell activation
induction of apoptosis
Meroni, Nature Rheumatology, 2011 Isfahan
Main Effects of aPL on Placenta 1391
Anti-β2GPI antibodies react with decidual cells
Induction of a proinflammatory phenotype

Umbilical Cord
Fetal Blodd
Vessels
Intravillous space

Mtaernal Blood vessels

Blood Vessels Decidua Trophoblast
58
Anti-β2GPI antibodies react with trophoblasts
aPL induced placental thrombosis
Inhibition of proliferation, differentiation;
Monocyte, Platelet, endothelial cell activation
induction of apoptosis
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LAB TESTS
IN
CLINICAL PRACTICE

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Who should be tested?

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Who should be tested?
• Connective tissue disease
• Thrombosis <45
• Arterial and venous thrombosis
• Thrombosis and fetal loss
• Family History
• Thrombosis in unusual sites
• Recurrent superficial thrombosis
• Recurrent miscarriage
• Warfarin- induced skin necrosis

Khamashta , Hughes Syndrome, 2006 61

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When?

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When?

Between 6 Weeks to 3 Months

After Thrombosis for Confirmation

Khamashta , Hughes Syndrome, 2006

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Which Tests Should be Measured?

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Which Tests Should be Measured?

• Triple aPL positivity Strong predictor of

Thrombosis

Semin Thromb Hemost 2012;38

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CLINICAL
MANIFESTATIONS

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DERMATOLOGIC 1391

MANIFESTATIONS
• Livedo Reticularis

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DERMATOLOGIC 1391

MANIFESTATIONS
• Livedo Racemosa

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 Isfahan
Livedo reticularis with necrotic 1391

finger tips

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LARGE VEESEL MANIFESTATIONS

• Venous Thrombosis
• Deep Vein Thrombosis
• Pulmonary Embolism

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LARGE VEESEL MANIFESTATIONS

• Arterial Thrombosis
• Stroke and TIAs are the most common

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NEUROLOGIC 1391

MANIFESTATIONS
• Cerebral Infarction
• Sinus Thrombosis
• Psychosis
• Cognitive Defects
• Migraine
• Epilepsy
• Chorea
• Transverse Myelopathy

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CARDIAC 1391

MANIFESTATIONS
• MI

• Cardiomyopathy

• Valvular Disease

− Mitral valve
− Diffuse valve thickening
− No chordal thickening
− No calcification
Khamashta , Hughes Syndrome, 2006

• Cervera
Pseudo-infective Endocarditis
, Antiphospholipis 73
Syndrome in Systemic Autoimmune Disease, 2009
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PULMONARY 1391

MANIFESTATIONS
• Pulmonary Embolism

• Major Pulmonary Arterial Thrombosis

• Pulmonary Microthrombosis

• Pulmonary Hypertension

Cervera , Antiphospholipis Syndrome in Systemic Autoimmune Disease, 2009

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KIDNEY 1391

MANIFESTATIONS
• Renal Vein Thrombosis

• Major Renal Artery Occlusion

• Renal Infarction

• Thrombotic Glomerular Microangiopathy

Cervera , Antiphospholipis Syndrome in Systemic Autoimmune Disease, 2009

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HEMATOLOGIC 1391

MANIFESTATIONS
• Thrombocytopenia
− 20-40%
− Usually Moderate
• Hemolytic Anemia

• Thrombotic Microangiopathic Hemolytic Anemia

• DIC
Cervera , Antiphospholipis Syndrome in Systemic Autoimmune Disease, 2009

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OBSTETRIC 1391

MANIFESTATIONS
• Early Miscarriage

• Fetal Death

• Preeclampsia and HELLP Syndrome

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CATASTROPHIC APS
• Involvement of ≥ 3 organs, systems, or tissues

• Simultaneous Manifestations or in < 1 week

• Histopathology Confirmation

• Laboratory Confirmation

Asherson, Lupus, 2005

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Differential Diagnosis
• Infection-induced anticardiolipin:

1. transient and is more commonly IgM than IgG.

2. Transient aPLs or low-titer anticardiolipin is nondiagnosis.

3. distinguish autoimmune from infection-induced aPLs by

determining the antibody’s β2GPI dependence.

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Fetal loss
• deficiency of protein C, protein S, and
antithrombin III
• presence of the factor V Leiden

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Fetal loss
• A single pregnancy loss before 10 weeks’
gestation in a patient with a low-positive
anticardiolipin test :

1. chromosomal abnormalities
2. infection
3. maternal hormonal or anatomic
abnormalities

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Thromboembolic events

• Hypertension
• diabetes
• nephrotic syndrome
• venous insufficiency
• immobility

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Arterial occlusion
• TTP
• emboli of cardiac or vascular origin
• septicemia
• Hyperhomocysteinemia
• Takayasu’s arteritis
• polyarteritis nodosa
• severe Raynaud’s disease

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Sneddon’s syndrome
• stroke and livedo reticularis
• with or without aPLs
• Hypertension

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Catastrophic APS

• Sepsis
• DIC
• TTP
• HUS
• PAN
• atherosclerosis

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MANAGEMENT

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MANAGEMENT of THROMBOSIS

• Primary Prevention

• Elimination of reversible risk factors

• Prophylaxis during high-risk periods

• ASA is no better than placebo

• so consider:
 Age
 Cardiovascular Risk Factors
 Systemic Autoimmune disease
 aPL profile
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Erkan, Nature Rhumatology, 2009
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MANAGEMENT of THROMBOSIS

• Secondary Prevention

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MANAGEMENT of THROMBOSIS 1391

Secondary Prevention
• High Vs. Low intensity anticoagulant

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MANAGEMENT of THROMBOSIS 1391

Secondary Prevention
• High Vs. Low intensity anticoagulant

− No Difference
Crowther, Arthritis Rheum, 2003
Finazzi, J Thromb hameost, 2005

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MANAGEMENT of THROMBOSIS 1391

Secondary Prevention
• High Vs. Low intensity anticoagulant

− No Difference
Crowther, Arthritis Rheum, 2003
Finazzi, J Thromb hameost, 2005

− They are different

Ruiz-Irastorza, Lupus, 2007
Cervera , Antiphospholipis Syndrome in
Systemic Autoimmune Disease, 2009
Lahita, Systemic Lupus Erythematosus, 2011
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MANAGEMENT of THROMBOSIS 1391

Secondary Prevention
• APS + First DVT INR 2-3

• APS + Arterial Event INR 3-4

• APS + Recurrent Event INR 3-4

• DVT + Single or Low-titer apl Like General population

• Arterial Thrombosis + Like General population

Ruiz-Irastorza, Lupus, 2007
Single or Low-titer apl Cervera , Antiphospholipis Syndrome in
Systemic Autoimmune Disease, 2009
Lahita, Systemic Lupus Erythematosus,932011
 Isfahan
MANAGEMENT of THROMBOSIS 1391

Secondary Prevention

No data for adding ASA for recurrent event

Ruiz-Irastorza, Lupus, 2007

Cervera , Antiphospholipis Syndrome in
Systemic Autoimmune Disease, 2009
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MANAGEMENT of OBSTETRIC 1391

MANIFESTATIONS
• Early Pregnancy Loss

− ASA alone
Or
− ASA+ Heparin (Prophylactic dose)

Khamashta, 8th European Lupus Meeting, Oral Presentation, 2011

Ruiz-Irastorza, Rhematic disease Clinics of North America, 2007

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MANAGEMENT of OBSTETRIC 1391

MANIFESTATIONS
• Late Pregnancy Loss

− ASA + Heparin (Prophylactic dose)

Khamashta, 8th European Lupus Meeting, Oral Presentation, 2011

Ruiz-Irastorza, Rhematic disease Clinics of North America, 2007

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MANAGEMENT of OBSTETRIC 1391

MANIFESTATIONS
• With History of Thrombosis

− ASA + Heparin (Therapeutic dose)

Ruiz-Irastorza, Rhematic disease Clinics of North America, 2007

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KELLEY’S TEXTBOOK OF RHEUMATOLOGY ,2013

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THANKS
FOR
YOUR ATTENTION

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