Anti-Phospholipid Syndrome (APS, “APLA”)
a prethrombotic syndrome
Diagnosis and management
‫דר' דפנה פארן‬
‫סגנית מנהל המחלקה ראומטולוגית‬
‫בי"ח איכילוב‬
Normal hemostasis
Disruption of vascular endothelial lining allows exposure of blood to
subendothelial connective tissue:
Primary hemostasis (seconds)
- Platelet plug formation at site of injury
- Stops bleeding from capillaries, small
arterioles and venules
Secondary hemostasis (minutes)
- Fibrin formation by reactions of
the plasma coagulation system
Bleeding and Thrombosis
Defects in primary hemostasis
• Thrombocytopenia
Defects in secondary hemostasis
• Clotting factor deficiencies
• Prethrombotic (hypercoagulable)
states
‫תרומבוציטופניה‬
‫תרומבוס‬
Prethrombotic disorders
• Inherited
• Acquired
Inherited prethrombotic disorders
• Anti-thrombin deficiency
• Deficiencies of protein C and S
• Resistance to activated protein C ( factor V Leiden mutation)
• Prothombin gene mutation ( G20210A)
• Homocystinemia
Acquired prethrombotic 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
The Antiphospholipid Syndrome
is characterized by:
• Arterial or Venous Thrombosis
• Recurrent Fetal Loss
• Serum Anti-phospholipid antibodies (aPL)
The Antiphospholipid Syndrome
may be:
• Primary:
an isolated condition
• Secondary:
secondary to SLE or other connective tissue
diseases
Nomenclature change:
•
APS - no associated rheumatic disease (50%)
•
APS - associated rheumatic disease
present in 10% of SLE patients
•
aPL - antiphospholipid antibodies (no symptoms)
•
CAPS - catastrophic APS ~ 238 worldwide reported cases
Clinical Presentations of APS
• Venous thromboembolism:
Deep Vein Thrombosis
Pulmonary Embolism
Clinical Presentations of APS
• Arterial Occlusion:
Stroke and TIAs are the most common
Clinical presentations of APS
Pregnancy morbidity
Recurrent fetal loss
• In women with recurrent miscarriage due to APS
fetal loss rate: as high as 90%
• antiphospholipid abs are associated with:
- placental insufficiency
- early preeclamapsia
- IUGR- intrauterine growth restriction
Antiphospholipid antibodies (aPL)
• anti-Cardiolipin IgG
• anti-Cardiolipin IgM
• Lupus anticoagulant (LAC)
* false positive VDRL
Epidemiology of antiphospholipid antibodies
• in the normal population:
2 - 12 %
prevalence increases with age and chronic disease
• in SLE:
30 - 40 %
LAC: 11-30% aCL: 24-86%
• in first Stroke:
10 - 26 %
• in recurrent fetal loss:
15 %
Antiphospholipid Syndrome Criteria
Sydney revision of Sapporo criteria 2006
CLINICAL CRITERIA
• Vascular Thrombosis
• 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
LABOARATORY CRITERA
• anti-Cardiolipin IgG
• anti-Cardiolipin IgM
• Lupus anticoagulant (LAC)
- medium - high titer
- at least X 2
- 12 wks apart
Definite APS: 1 Clinical + 1 Lab criteria
Sydney Revision of Sapporo criteria (2006)
• Clinical Criteria
- Thrombosis:
exclude other causes : male > 55 yrs
female > 65 yrs
- Pregnancy:
placental insufficiency < 34 wks
exclude other causes
Sydney Revision of Sapporo criteria (2006)
• Laboratory Criteria
- medium/high titer IgG or IgM aCL on 2 occasions
12 wks apart
- LAC on 2 occasions 12 wks apart
Sydney Revision of Sapporo criteria (2006)
aPL associated manifestations (individual diagnosis)
•
•
•
•
Thrombocytopenia ( occurs in up to 50%)
Cardiac valve disease
Livedo reticularis
Nephropathy ( late manifestation)
Livedo reticularis
Livedo reticularis with necrotic finger tips
in Antiphospholipid syndrome
Possible Clinical Presentations of APS
not included in criteria
•
•
•
•
•
Transverse myelitis
Migraine
Chorea
Leg ulcers
UBOs (white matter lesions) on brain MRI
“Antiphospholipid” antibodies
antibodies and antigens
• Most of the abs are NOT directed against phospholipids
• Most of the antiphospholipid abs recognize
phospholipid binding proteins:
- beta 2 glycoprotein I (b2 GPI)
- prothrombin
Beta 2 Glycoprotein-I
(b2GPI)
 b2GPI = a plasma protein with affinity for
negatively charged phospholipids
• anti- b2GPI:
are probably the major cause of APS
Antibodies and antigens
• Anticardiolipn abs recognize in most assays:
b2 GPI
• Lupus Anticoagulant activity is caused by
autoantibodies to:
- b2 GPI
- prothrombin
Laboratory Testing for antiphospholipid antibodies
• Solid phase assays
usually anti-Cardiolipin abs
• Lupus Anticoagulant (LAC)
MUST USE BOTH TESTS
Lupus Anticoagulant Tests
Coagulation Assays
• Perform coagulation screen to detect prolongation
in phospholipid dependent coagulation assay (usually use: APTT)
• If APTT is prolonged: Mix with normal plasma
- If due to factor deficiency: corrected
- If due to inhibitor (antibody) not corrected
• Confirm inhibitor is phospholipid dependent :
corrected by mixing with platelets or phospholipids
• Perform second test: KCT or DRVVT
Tests for LAC
No LAC shows 100% specificity
and sensitivity because aPLs are
heterogeneous.
More than 1 test system is
needed
• APTT:
- variability in reagents result in inconsistent sensitivity.
- acute phase reaction and pregnancy may shorten APTT and mask
a weak LAC
A normal APTT does not exclude LAC
• KCT- Kaolin clotting time
more sensitive to presence of anti-II
• DRVVT- Dilute Russell’s viper venom time
more sensitive to presence of b2 GPI
• TTI - Tissue thromboplastin inhibition test
Possible mechanisms of aPL induced thrombosis
• Endothelial-aPL interaction
endothelial cell damage or activation, coexisting anti-endothelial abs,
aPL induced monocyte adhesion,
increased tissue factor expression
• Platelet-aPL interaction
platelet activation, stimulation of thromboxane production
• Coagulation system-aPL interaction
inhibition of activation of protein C , interaction between aPL and
substrates of activated protein C: factors Va VIIIa; interaction between
aPL and annexin V anticoagulant shield
• Complement activation
Anticoagulation by direct or indirect thrombin
inhibition
AGENT
COMPLEMENT
PREGNANCY
Heparin
Inhibits
protects
Fondaparinux
No effect
does not protect
Hirudin
No effect
does not protect
Occurrence of antiphospholipid antibodies in other
conditions:
• Infection:
- 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
Indications for Laboratory testing for antiphospholipid abs
• Spontaneous venous thromboembolism
• Recurrent VT, even in presence of other risk factors
• Stroke or peripheral arterial occlusive event at < 50 yrs
• In all SLE patients
• In women with > 3 consecutive pregnancy losses
loss of morphologically normal fetus at II-III trimester
early severe preeclampsia
severe placental insufficiency low prevalence in general obstetric
population (< 2% ): screening not warranted
Management of the Antiphospholipid
Syndrome
Incidental finding of antiphospholipid antibodies
• Anti-thrombotic therapy not usually indicated
• Low threshold for thromboprophylaxis at times of high risk
• Some suggest low dose Aspirin prophylaxis
• Reduce other risk factors for thrombosis
Venous or Arterial thrombosis
1. Initial treatment with Heparin
2. Start Warfarin
3. Stop Heparin when therapeutic INR achieved
Current Recommendations
•
•
•
•
Asymptomatic aPL
Venous thrombosis
Arterial thrombosis
Recurrent thrombosis
• CAPS
no treatment (Aspirin?)
Warfarin INR 2.0-3.0
Warfarin INR 3.0
Warfarin INR 3.0-4.0 + Aspirin
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
Management of aPL positive patients with adverse
pregnancy history
• Poor obstetric history - the most important predictor
• The risk of fetal loss is related to aCL ab titer
• Presence of aPL are a marker for a high risk pregnancy
• Once APS is diagnosed, serial aPL testing is not useful
Current Recommendations
Pregnancy
• Asymptomatic aPL
• Single loss <10wks
• Recurrent loss* <10wks
Fetal protection
no treatment
no treatment
prophylactic heparin +ASA
up to 6-12 wks postpartum, ASA after(?)
• Recurrent loss < 10 wks
+ thrombosis
therapeutic heparin + ASA,
warfarin postpartum
• Prior thrombosis
therapeutic heparin + ASA
warfarin postpartum
* Late fetal loss
IUGR
severe pre-eclampsia
Heparin and aspirin for recurrent miscarriage
without history of thrombosis
• for recurrent miscarriage :
improved live birth rate from 40% to 70-80%
• for late losses or intrauterine death:
results in 70-75% live birth
Other therapies for aPL associated 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
Fetal Monitoring
• US monitoring of fetal growth and amniotic fluid
every 4 weeks
• US monitoring of uteroplacental blood flow: uterine
artery waveforms assessed at 20-24 wks
• If early diastolic notch seen: do 2 weekly growth scans
due to high risk of IUGR
Antiphospholipid Syndrome
Summary
• Due to the wide spectrum of manifestations any
physician 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.
Case description
• 35 year old male, single
• Presented with:
- sudden vision loss- rt eye:
due to Central retinal vein occlusion
- Chronic leg ulcer
Past Medical History
• S\P Lt lower Leg DVT
• S\P CVA with Lt. hemiparesis
• Hypertension
Physical examination
•
•
•
•
•
•
Marked cognitive impairment
Unstable gait
Lt. mild spastic hemiparesis
Rt. blind eye
Edematous left calf with venous stasis
Large chronic leg ulcer- lt calf
• ANA- negative
Laboratory work-up
• Anti-DNA- negative
• Anticardiolipid IgG > 120 GPLU (N<10)
(x2)
• Anticardiolipin IgM - normal
• Anti-b2 glycoprotein I > 100
• Lupus anticoagulant – negative
(N<8)
(x2)
Diagnosis
Primary Antiphospholipid syndrome with:
- recurrent arterial thrombosis: CVA
leg ulcer
- recurrent venous thrombosis: DVT
CRV occlusion
- High titer antiphospholipid antibodies: anticardiolipin IgG
anti-b2 GPI
Management and course
• Coumadin: INR = 3.0
• Gradual complete healing of leg ulcer
• No further thrombotic episodes
• Some improvement in gait and cognition