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OBGYN
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Antiphospholipid syndrome was
described in full in the 1980s, after
various previous reports of specific
antibodies in people with systemic lupus
erythematosus and thrombosis.
The syndrome is sometimes referred to as "Hughes syndrome",
after the rheumatologist Dr. Graham R.V. Hughes who worked
at the Louise Coote Lupus Unit at St Thomas' Hospital in London
and played a central role in the description of the condition.
In young,app healthy people---for LA, antiCL is 1-5%
Prevalence ↑ with age ,in elderly with chronic disease.
Mean age of onset-31 yrs,Low age 8 months
Risk of thrombosis is 0.5-30%
Women :men is 5:1
Females---arthritis,livedo,migraine
Males—MI,epilepsy,lower extremity arterial thrombosis
More common in african americans.
Without rheumatic disease at younger age and
with rh –older
Apl ab—30-40% in SLE---10% have APLS
Idiopathically—ACL-24%,LA-4%
Antiphospholipid syndrome or antiphospholipid antibody
syndrome (APS or APLS or), often also Hughes syndrome,
is an autoimmune, hypercoagulable state caused by antibodies
against cell-membrane phospholipids that provokes blood clots
(thrombosis) in both arteries and veins as well as
pregnancy-related complications such as
miscarriage, stillbirth, preterm delivery, or severe preeclampsia.
The syndrome occurs due to the autoimmune production of
antibodies against phospholipid (aPL), a cell membrane substance.
In particular, the disease is characterised by antibodies against
cardiolipin (anti-cardiolipin antibodies) and β2 glycoprotein I.
Risk factors for developing antiphospholipid syndrome include:•Primary APS
genetic marker HLA-DR7•Secondary APS
SLE or other autoimmune disordersGenetic markers: HLA-B8, HLA-DR2, HLA-DR3Race: Blacks, Hispanics, Asians, and Native Americans
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
Defects in primary hemostasis
Thrombocytopenia
Defects in secondary
hemostasis
Clotting factor
deficiencies
Prethrombotic(hypercoagulable) states
Inherited
Acquired
• Anti-thrombin deficiency
• Deficiencies of protein C and S
• Resistance to activated protein C •( factor V Leiden mutation)
• Prothombin gene mutation• ( G20210A)
Homocystinemia
Conditions associated with a hypercoagulable state:
- pregnancy and postpartum - major surgery- obesity and immobility - malignancy- congestive heart failure- nephrotic syndrome
Estrogen treatment
Antiphospholipid syndrome
Antiphospholipid syndrome is an autoimmune disease, in which
"antiphospholipid antibodies" :
1.anticardiolipin antibodies (ACA)
2. lupus anticoagulant(LA)
react against proteins that bind to anionic phospholipids on
plasma membranes.
ACA– are directed against cardiolipin
They may be b2 gp1 dependent or independent
(Independent—syphilis)
B2 gp1-----apolipoprotein H
Bind with cardiolipin ab - thrombosis
• b2GPI a plasma protein with affinity for negatively charged phospholipids
• anti- b2GPI: are probably the major cause of APS
Anticardiolipn abs recognize in most assays: b2 GPI
Lupus Anticoagulant activity is caused by autoantibodies to:
- b2 GPI
- prothrombin
Anionic phospholipids
The exact cause is not known, but
activation of the system of coagulation is
evident.
Homeostatic regulation of blood coagulation is altered.
1.defect in cellular apoptosis- exposure of membrane phospholipids to the binding of various plasma proteins---b2gp1---
complex—epitope---target for autoantibodies.
2.oxidized b2GP1---activates dendritic cells –autoantibodies are
produced.
3.production of antibodies against prothrombin, proteinC, S
annexins.
4.activation of platelets to enhance endothelial adherence.
5.activation of vascular endothelium—platelet and monocyte
binding.
6.ab against oxidized LDL — atherosclerosis.
Complement activation has been increasingly recognised as a
possible significant role in the pathogenesis of APS.
The family of APL ab are heterogenous and the targets vary.
APS can be caused by –LA,ACA,B2GP1 or other antibodies.
There are distinct clinical ,laboratory and biochemical differences
between the disorders mediated by the different antibodies.
ACL---risk of stroke—arterial thrombosis
LA-venous
TNF alpha –pregnancy loss
Coagulation pathway
Annexin ˅
The syndrome can be divided into primary (no underlying disease state)
and secondary (in association with an underlying disease state) forms.Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH, which in turn inhibits Protein C, a glycoprotein with regulatory function upon the common pathway of coagulation (by degradating activated factor V).
Clinically important antiphospholipid antibodies (those that
arise as a result of the autoimmune process) are associated
with thrombosis and vascular disease.
LAC antibodies bind to prothrombin , thus increasing its cleavage to thrombin, its active form .In APS there are also antibodies binding to: Protein S, which is
a co-factor of protein C.
Thus, anti-protein S antibodies decrease protein C efficiency;
Annexin A5, which forms a shield around negatively-charged
phospholipid molecules, thus reducing their availability for
coagulation.
Thus, anti-annexin A5 antibodies increase phospholipid-
dependent coagulation steps.
The Lupus anticoagulant antibodies are those that show the closest
association with thrombosis, those that target β2glycoprotein 1 have a
greater association with thrombosis than those that target prothrombin.
Anticardiolipin antibodies are
associated with thrombosis
at moderate to high titres
(>40 GPLU or MPLU).
Patients with both Lupus anticoagulant antibodies and moderate/high titre
anticardiolipin antibodies show a greater risk of thrombosis than with one
alone .
APL antibodies and NF-B
Intracellular events in EC induced by aPL antibodies:
aPL induce activation of NF-B and correlates with EC activation in vitro and in vivo and with thrombosis in vivo. Espinola RG et al: J Thromb Haemost, 2003; 1: 843-
848.
Dunoyer-Geindre S. et al. Thromb Haemost. 2002; 88: 851-857.
Bohgaki M, et al. Int Immunol. 2004; 16: 1632-1641.
Pathogenesis
In Pregnancy
This Syndrome is characterized by:
Arterial or Venous Thrombosis
Thrombocytopenia
Recurrent Fetal Loss
Serum Anti-phospholipid antibodies (aPL)
1. Primary antiphospholipid syndrome
APS occurs in the absence of any other related disease.
2. Secondary antiphospholipid syndrome
APS occuring in the context of other autoimmune
diseases, such as systemic lupus erythematosus (SLE).
3. Catastrophic antiphospholipid syndrome
In rare cases, APS leads to rapid organ failure due to
generalised thrombosis; this is termed (CAPS) and is
associated with a high risk of death.
Venous Thromboembolism: Arterial Occlusion: Stroke and TIAs are
the most common
Pulmonary Embolism
Deep Vein Thrombosis
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
Pregnancy Morbidity
aPL associated
manifestations (individual
diagnosis)
Thrombocytopenia
(occurs in up to 50%)
Cardiac valve disease
Livedo reticularis
Nephropathy ( late
manifestation)
Sydney revision of Sapporo criteria 2006
Livedo reticularis with necrotic finger tips in
Antiphospholipid syndrome
Transverse Myelitis
Migraine
Chorea
Leg ulcers
UBOs (white matter lesions) on brain MRI
not included in criteria
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
Common auto immune diseases ass with APL ab are
1.SLE-25-50%
2.sjogren’s –42%
3.RA-33%
4.AITP-30%
5.AIHA-unknown
6.MCD-22%
7.behcet-20%
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
APA---IgG,IgA,IgM
SEVERAL antibodies are recognised
Recently—antibodies against annexin V,protein C
IgM acl---HEMOLYTIC ANEMIA.
IgG ACL –thrombosis
False positive test result for syphilis
ACL—membrane phospholipids
LA-plasma coagulation molecules
Elongates APTT,Kaolin clotting time,dilute russells viper venom time.
Advantages
Overwhelming majority of APS patients are anti cardiolipin positive
Test can be performed reproducibly.
Clinicians and laboratories generally familiar with units of measurement.
Disadvantages
Relatively nonspecific (particularly low positive, IgM positive).
Intra-laboratory and Inter-laboratory variability.
Problems with false positive results: aCL positive in a wide variety of infectious diseases and in non-APS related autoimmune diseases.
Solid phase assays usually anti-Cardiolipin abs
IgG aCL levels below 21.4 = probability of thrombosis 0.07
IgG aCL levels >21.4 and < 65.0 GPL = probability of
thrombosis 0.20
IgG aCL levels >65.1 GPL units = probability of thrombosis
0.75
Predictive value of IgG aCL for thrombosis in patients with SLE
Perform coagulation screen to detect prolongationin 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
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
No LAC shows 100% specificity and
sensitivity because aPLs are heterogeneous.
More than 1 test system is needed
Diluted Russells viper venom test
Kaolin Clotting Test
Based on observation that antiphospholipid antibodies cross-react with
negatively charged phospholipids but syphilis and other infectious diseases
sera largely limited to cardiolipin binding (no cross-reactivity)
Construction of a kit with negatively charged phospholipids might eliminate non-specific binding.
Antigen composed of mixture of phospholipids instead of cardiolipin
Sensitivity of APS (greater than 90%)
More specific than anticardiolipin test and at least as specific (or more) compared to anti-ß2GPI
Incorporation of an in-house positive control
Can be utilized for first line testing, and certainly important in confirmation of APS
Principle
Patient Laboratory Data
PT 20.6 sec aPTT 100.3 sec
TCT 8.8 sec DRVVT ‘No clot’
Factor VIII ‘Inhibitory’ Factor IX <1.6%
Factor XI <1.6% Bethesda titer 2.8 U
Platelets 120,000/ml Factor X 68%
Additional Laboratory Data
Factor V (aPTT) “Inhibitory”
Factor V (PT) 115%
Factor II 38%
Fibrinogen 795.6 mg/dl
D-dimer >4.37 mcg FEU/ml
Repeat DRVVT (ratio) 3.23
DRVVT Confirm (ratio) 2.17
Alternative strategies to
identify a lupus anticoagulant
Platelet neutralization procedure (PNP; uses platelet
membranes).
Hexagonal phase phospholipid assay (StaClot LA; uses PE
in a hexagonal phase conformation).
Textarin/Ecarin clot time.
Factor V analysis by PT and aPTT-based assays.
What if LA,ACL are negative
If patient experiencing thrombosis or recurrent miscarriages
Order
Antibodies to b2 gp1
Ab to phosphatidylserine,ethonalamine,glycerol,inositol
Annexin V
Phosphatidyl choline.
Imaging studies
For confirmation
USG
COLOR DOPPLER
CT SCAN
MRI
2D ECHO
Histology----
non inflammatory bland thrombosis with no signs of
perivascular inflammation or leukocytoclastic vasculitis.
Lupus anticoagulant detected and confirmed.
Multiple factor deficiencies in aPTT pathway reflect high-titer lupus
anticoagulant.
Prolonged PT reflects mild factor II deficiency and lupus anticoagulant
effect.
Elevated D-dimer reflects recent thrombosis.
Elevated inhibitor titer due to lupus anticoagulant.
DIFFERENTIAL DIAGNOSIS
Think of any other thrombophilic states before making a diagnosis of APLS.
Malignancy
OCP
Homocysteinemia
Antithrombin 111 def
Protein C,S def
Factor V leiden mutation
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
INR
The ISI—1.0-2.0
INR—5 high chance of bleeding
0.5--- clot formation
Normal range is 0.9-1.3
Warfarin ---2.0-3.0
Prosthetic valves—3.0-4.0
• Eliminate other risk factors, such as oral contraceptives,
smoking, hypertension, or hyperlipidemia.
• Low-dose aspirin is used widely in this setting; however, the
effectiveness of low-dose aspirin as primary prevention for
APS remains unproven.
• Clopidogrel has anecdotally been reported to be helpful in
persons with APS and may be useful in patients allergic to
aspirin.
• In patients with SLE, consider hydroxychloroquine, which
may have intrinsic antithrombotic properties.
•Consider the use of statins, especially in patients with
hyperlipidemia.
Prophylactic therapy
• Perform full anticoagulation with intravenous or
subcutaneous heparin followed by warfarin therapy.
• Based on the most recent evidence, a reasonable
target for the international normalized ratio (INR) is 2.0-3.0
for venous thrombosis and 3.0 for arterial thrombosis.
• Patients with recurrent thrombotic events, while well
maintained on the above regimens, may require an INR
of 3.0-4.0.
• For severe or refractory cases, a combination of
warfarin and aspirin may be used.
•Treatment for significant thrombotic events in patients
with APS is generally lifelong.
Thrombosis
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 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 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
FOLLOW UP
Frequent check ups
Adequate patient education
Avoidance of smoking
Strict control with anticoagulants.
In case of bleeding –hospital.
Normal healthy life
With appropriate medication and lifestyle modifications, most
individuals with primary antiphospholipid syndrome (APS) lead
normal healthy lives.
However, subsets of patients continue to have thrombotic events
despite aggressive therapies. In these patients and in patients with
CAPS, the disease course can be devastating, often leading to
significant morbidity or early death.
A retrospective study suggested that hypertension or medium-to-high titers of IgG anticardiolipin antibody are risk factors for a first
thrombotic event in asymptomatic patients with antiphospholipid
(aPL) antibodies.[18] Primary prophylaxis against thrombosis appears to offer significant protection in such cases.
Prognosis
Patients with secondary APS carry a prognosis similar to that of
patients with primary APS; in the former, however, morbidity and
mortality may also be influenced by these patients' underlying autoimmune or rheumatic condition. In patients with SLE and APS,
aPL antibodies have been associated with neuropsychiatric disease
and have been recognized as a major predictor of irreversible organ
damage.
Women with aPL antibodies who experience recurrent miscarriages may have favorable prognoses in subsequent pregnancies if treated
with aspirin and heparin.
Future Directions
Can? we predict which patients with antiphospholipid antibodies will
develop thromboembolic complications?
Is there an inherited predisposition to developing antiphospholipid
antibody syndrome
Genomic strategy
Whole blood RNA prepared using PAXgene system from patients
with APS and selected control populations.
RNA extracted and validated.
Oligonucleotide arrays printed at the Duke Microarray Facility,
using the Operon Human Genome Oligo Set Version 3.0 (Operon,
Huntsville, AL).
-- Potti, et al., Blood, 2006; 107: In press.
Discovery ModePreliminary data with patients and ‘controls’
Controls with VTE APS NormalaPLA
Up regulated Down regulated
Family history
Asymptomatic
daughter tests
positive for a
lupus
anticoagulant.
Mother developed
arterial thrombosis
and
thrombocytopenia
prior to her death.
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.