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Antiphospholipid syndrome By Dr.Rozan
1.
2. Antiphospholipidsyndrome was
described in full in the 1980s, after
various previous reports of specific
antibodies in people with systemic lupus erythematosusand thrombosis.
The syndrome is sometimes referred toas "Hughes syndrome", after the rheumatologistDr. Graham R.V. Hughes who worked at the Louise CooteLupus Unit at St Thomas' Hospitalin London and played a central role in the description of the condition.
3. In young,apphealthy people---for LA, antiCLis 1-5%
Prevalence ↑ with age,in elderly with chronic disease.
Mean age of onset-31 yrs,Lowage 8 months
Risk of thrombosis is 0.5-30%
Women :men is 5:1
Females---arthritis,livedo,migraine
Males—MI,epilepsy,lowerextremity arterial thrombosis
More common in africanamericans.
Without rheumatic disease at younger age and
with rh–older
Aplab—30-40% in SLE---10% have APLS
Idiopathically—ACL-24%,LA-4%
4. Antiphospholipidsyndromeor antiphospholipidantibody
syndrome(APS or APLS or), often also Hughes syndrome,
is an autoimmune, hypercoagulablestate caused by antibodies
against cell-membrane phospholipidsthat provokes blood clots
(thrombosis) in botharteriesand veinsas well as
pregnancy-related complications such as
miscarriage, stillbirth, preterm delivery, or severe preeclampsia.
The syndrome occurs due to the autoimmuneproduction of
antibodiesagainst phospholipid(aPL), a cell membranesubstance.
In particular, the disease is characterisedby antibodies against
cardiolipin(anti-cardiolipinantibodies) and β2glycoprotein I.
5. Risk factors for developing antiphospholipidsyndrome include:
•Primary APS
genetic markerHLA-DR7
•Secondary APS
SLEor other autoimmune disorders
Genetic markers: HLA-B8, HLA-DR2, HLA-DR3
Race: Blacks, Hispanics, Asians, and Native Americans
6. Disruption of vascular endothelial lining allows exposure of blood to subendothelialconnective 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
7. Defects in primary hemostasis
Thrombocytopenia
Defects in secondary hemostasis
Clotting factor deficiencies
Prethrombotic(hypercoagulable) states
9. •Anti-thrombin deficiency
•Deficiencies of protein C and S
•Resistance to activated protein C
•( factor V Leiden mutation)
•Prothombingene mutation
•( G20210A)
Homocystinemia
Conditions associated with a hypercoagulablestate:
-pregnancy and postpartum
-major surgery
-obesity and immobility
-malignancy
-congestive heart failure
-nephroticsyndrome
Estrogen treatment
Antiphospholipidsyndrome
10. Antiphospholipidsyndrome is an autoimmune disease, in which "antiphospholipidantibodies" :
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)
11. B2 gp1-----apolipoproteinH
Bind with cardiolipinab-thrombosis
•b2GPIa plasma protein with affinity for negatively charged phospholipids
•anti-b2GPI: are probably the major cause of APS
Anticardiolipnabsrecognize in most assays: b2 GPI
Lupus Anticoagulantactivity is caused by autoantibodies to:
-b2 GPI
-prothrombin
12. Anionic phospholipids
The exact causeis not known, but activation of the system of coagulation is evident.
13.
14. 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 antibodiesagainst 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.
15. Complement activation has been increasingly recognisedas a possible significant role in the pathogenesis of APS.
The family of APL abare heterogenousand 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
17. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms.
Anti-ApoHand a subset of anti-cardiolipinantibodies bind to ApoH, which in turn inhibits Protein C, a glycoproteinwith regulatory function upon the common pathway of coagulation (by degradatingactivated factor V).
Clinically important antiphospholipidantibodies (those that arise as a result of the autoimmune process) are associated with thrombosis and vascular disease.
18. 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;
AnnexinA5, which forms a shield around negatively-charged phospholipid molecules, thus reducing their availability for coagulation.
Thus, anti-annexinA5 antibodies increase phospholipid- dependent coagulation steps.
19. 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.
Anticardiolipinantibodies are
associated with thrombosis
at moderate to high titres
(>40 GPLU or MPLU).
Patients with both Lupus anticoagulant antibodies and moderate/high titreanticardiolipinantibodies show a greater risk of thrombosis than with one alone .
20. APL antibodies and NF-B
Intracellular events in EC induced by aPLantibodies:
aPLinduce activation of NF-Band correlates with EC activation in vitroand in vivoand with thrombosis in vivo.
EspinolaRG et al: J ThrombHaemost, 2003; 1: 843- 848.
Dunoyer-GeindreS. et al. ThrombHaemost. 2002; 88: 851-857.
BohgakiM, et al. IntImmunol. 2004; 16: 1632-1641.
23. This Syndrome is characterized by:
Arterial or Venous Thrombosis
Thrombocytopenia
Recurrent Fetal Loss
Serum Anti-phospholipidantibodies (aPL)
24. 1. Primary antiphospholipidsyndrome
APS occurs in the absence of any other related disease.
2. Secondary antiphospholipidsyndrome
APS occuringin the context of other autoimmune
diseases, such as systemic lupus erythematosus(SLE).
3. Catastrophic antiphospholipidsyndrome In rare cases, APS leads to rapid organ failure due to generalisedthrombosis; this is termed (CAPS) and is associated with a high risk of death.
26. Recurrent fetal loss
In women with recurrent miscarriage due to APS fetal loss rate: as high as 90%
antiphospholipidabs are associated with:
-placental insufficiency
-early preeclamapsia
-IUGR-intrauterine growth restriction
Pregnancy Morbidity
27.
28. aPLassociatedmanifestations (individual diagnosis)
Thrombocytopenia (occurs in up to 50%)
Cardiac valve disease
Livedoreticularis
Nephropathy ( late manifestation) Sydney revision of Sapporo criteria 2006
Livedoreticulariswith necrotic finger tipsin Antiphospholipidsyndrome
30. 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
31. Common auto immune diseases ass with APL abare
1.SLE-25-50%
2.sjogren’s –42%
3.RA-33%
4.AITP-30%
5.AIHA-unknown
6.MCD-22%
7.behcet-20%
32.
33. 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
lowprevalence in general obstetric
population (< 2% ): screening not warranted
34. APA---IgG,IgA,IgM
SEVERAL antibodies are recognised
Recently—antibodies against annexinV,proteinC
IgMacl---HEMOLYTIC ANEMIA.
IgGACL –thrombosis
False positive test result for syphilis
ACL—membrane phospholipids
LA-plasma coagulation molecules
Elongates APTT,Kaolinclotting time,diluterussellsviper venom time.
35. Advantages
Overwhelming majority of APS patients are anti cardiolipinpositive
Test can be performed reproducibly.
Clinicians and laboratories generally familiar with units of measurement.
Disadvantages
Relatively nonspecific (particularly low positive, IgMpositive).
Intra-laboratory and Inter-laboratory variability.
Problems with false positive results: aCLpositive in a wide variety of infectious diseases and in non-APS related autoimmune diseases.
37. IgGaCLlevels below 21.4 = probability of thrombosis 0.07
IgGaCLlevels >21.4 and < 65.0 GPL = probability of thrombosis 0.20
IgGaCLlevels >65.1 GPL units = probability of thrombosis 0.75
Predictive value of IgGaCLfor thrombosis in patients with SLE
38. Perform coagulation screen to detect prolongationin phospholipiddependent 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
39. 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 thromboplastininhibition test
No LAC shows 100% specificity and sensitivity because aPLsare heterogeneous. More than 1 test system is needed
42. Based on observation that antiphospholipidantibodies cross-react with negatively charged phospholipids but syphilis and other infectious diseases sera largely limited to cardiolipinbinding (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 anticardiolipintest 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
43. 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%
44. 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
45. Alternative strategies to identify a lupus anticoagulant
Platelet neutralization procedure (PNP; uses platelet membranes).
Hexagonal phase phospholipidassay (StaClotLA; uses PE in a hexagonal phase conformation).
Textarin/Ecarinclot time.
Factor V analysis by PT and aPTT-based assays.
46. What if LA,ACL are negative
If patient experiencing thrombosis or recurrent miscarriages
Order
Antibodies to b2 gp1
Abto phosphatidylserine,ethonalamine,glycerol,inositol
AnnexinV
Phosphatidylcholine.
47. Imaging studies
For confirmation
USG
COLOR DOPPLER
CT SCAN
MRI
2D ECHO
Histology----
non inflammatory bland thrombosis with no signs of perivascularinflammation or leukocytoclasticvasculitis.
48. Lupus anticoagulant detected and confirmed.
Multiple factor deficiencies in aPTTpathway reflect high-titer lupus anticoagulant.
Prolonged PT reflects mild factor II deficiency and lupus anticoagulant effect.
Elevated D-dimerreflects recent thrombosis.
Elevated inhibitor titer due to lupus anticoagulant.
49. DIFFERENTIAL DIAGNOSIS
Think of any other thrombophilicstates before making a diagnosis of APLS.
Malignancy
OCP
Homocysteinemia
Antithrombin111 def
Protein C,S def
Factor V leidenmutation
50.
51. Incidental finding of antiphospholipidantibodies
Anti-thrombotic therapy not usually indicated
Low threshold for thromboprophylaxisat times of high risk
Some suggest low dose Aspirin prophylaxis
Reduce other risk factors for thrombosis
52. 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
53. •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.
•Clopidogrelhas 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
54. •Perform full anticoagulation with intravenous or subcutaneous heparin followed by warfarintherapy.
•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
55.
56.
57.
58. Mild to moderate-Platelets > 50,000: No treatment
Severe-<50,000:
-corticosteroids -corticosteroid resistant cases:
HCQ , IVIG, Immunosuppressive drugs, Splenectomy
59. Management of aPLpositive patients with adverse pregnancy history
Poor obstetric history -the most important predictor
The risk of fetal loss is related to aCLabtiter
Presence of aPLare a marker for a high risk pregnancy
Once APS is diagnosed, serial aPLtesting is not useful
60. Current Recommendations
PregnancyFetal protection
Asymptomatic aPLno 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 warfarinpostpartum
Prior thrombosis therapeutic heparin + ASA
warfarinpostpartum
* Late fetal loss
IUGR
severe pre- eclampsia
61. Other therapies for aPLassociated 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
62. Fetal Monitoring
US monitoring of fetal growth and amniotic fluid
every 4 weeks
US monitoring of uteroplacentalblood 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
63. FOLLOW UP
Frequent check ups
Adequate patient education
Avoidance of smoking
Strict control with anticoagulants.
In case of bleeding –hospital.
Normal healthy life
64.
65. With appropriate medication and lifestyle modifications, most individuals with primary antiphospholipidsyndrome (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 IgGanticardiolipinantibody 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
66. 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, aPLantibodies have been associated with neuropsychiatric disease and have been recognized as a major predictor of irreversible organ damage.
Women with aPLantibodies who experience recurrent miscarriages may have favorable prognoses in subsequent pregnancies if treated with aspirin and heparin.
67. Future Directions
Can? we predict which patients with antiphospholipidantibodies will develop thromboembolic complications?
Is there an inherited predisposition to developing antiphospholipidantibody syndrome
68. Genomic strategy
Whole blood RNA prepared using PAXgenesystem 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 OligoSet Version 3.0 (Operon, Huntsville, AL).
--Potti, et al., Blood, 2006; 107: In press.
69. Discovery ModePreliminary data with patients and ‘controls’
Controls with VTE
APS
Normal
aPLA
Up regulated
Down regulated
70. Family history
Asymptomatic
daughter tests
positive for a
lupus
anticoagulant.
Mother developed
arterial thrombosis
and
thrombocytopenia
prior to her death.
71. Familial AntiphospholipidSyndrome
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.