2. INTRODUCTION
THROMBOSIS IS HEMOSTASIS IN WRONG PLACE
Antiphospholid syndrome(APS) is an autoimmune disorder
which manifests clinically as recurrent arterial or venous
thrombosis and/or fetal loss.
Characteristic lab abnormality exists as antibodies directed
against membrane anionic phospholipids( anticardiolipin
antibody,antiphosphatidylserine) or
their assocaited plasma protiens (beta 2 glycoprotein I).
3. Also known as
HUGHES SYNDROME named after
Graham Hughes.
Antiphospholipid antibody syndrome
LUPUS ANTI COAGULANT SYNDROME (misnomer)
Mostly assosciated with SLE.
Responsible for frequent miscarriages in young females (15%).
4. 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.
5. EPIDEMIOLOGY
In healthy people---frequency of aPL antibodies is 1-5 %
Prevalence ↑ with age ,in elderly with chronic disease.
Risk of thrombosis is 0.5-30%
SEX-Women :men is 5:1
AGE- Young and middle age adults
RACE- African american and Hispanics
Females---arthritis,livedo,migraine
Males—MI,epilepsy,lower extremity arterial thrombosis
Apl ab—30-40% in SLE---10% have APLS
aPL syndrome is the cause of
14 % of all strokes
11 % of all MI
10% of DVT
6% of pregnancy morbidity
9% of pregnancy lossses
6. Etiology
Although aPL antibodies are clinically linked to APS
whether they are invoved in pathogenesis is unclear
Possible triggers identified
Infections (via molecular mimicry)
Syphilis
Hepatitis C infection
HIV
Malaria
Bacterial septicemia
Drugs- Procainamide, Quinidine, propranolol, hydralazine,
phenytoin, chlorpromazine, quinine
Genetic predisposition- HLA –DRW53,DR7—HISPANIC
DR4 - white.
7. Antiphospholipid syndrome is an autoimmune disease, in which
"antiphospholipid antibodies" :
1.anticardiolipin antibodies (ACA)
2. lupus anticoagulant(LA)
3. Anti beta-2 glycoprotien 1 antibodies
They may be b2 gp1 dependent (aotuimmune aPLs) or
independent(infection and drug induced aPLs)
The presence of aPL, may be demonstrated directly by:
•Serum assays (ELISA)--- anticardiolipin antibody(ACA) and
-----anti beta2-glycoprotein (GP) I antibody
•Clotting assay ----- effects of an aPL on the phospholipid-dependent factors
in the coagulation cascade (lupus anticoagulant [LA] test)
9. PATHOPHYSIOLOGY
The family of APL ab are heterogenous and the targets vary.
Under physiologic conditions B2GPI act as elimination of
apoptotic cells and as natural anticoagulant.
There are distinct clinical ,laboratory and biochemical
differences between the disorders mediated by the different
antibodies.
ACL---risk of stroke—arterial thrombosis
LA---venous thrombosis
TNF alpha and complement activation –pregnancy loss
10. Activation or defective
apoptosis of platelets,
endothelial cells or
trophoblasts
Phosphatidylserine or
cardiolipin( negatively
charged phospholipid)
migrates to outer cell
surface
Circulating B2Gp1 bind
to phosphhatidylserine
aPL antibodies bind to
B2 Gp1 dimer
Activation of complement(C5a) and release of
cytokines(TNF alpha)
via migration of inflammatory cells produces a
prothrombotic state
12. Homeostatic regulation of blood coagulation is altered.
Defect in cellular apoptosis---exposure of membrane phospholipids to
the binding of various plasma proteins---b2gp1 complex,
neoepitope---target for autoantibodies.
Oxidized b2GP1---activates dendritic cells –autoantibodies are
produced.
Emerging evidence from animal studies suggest that aPLmediate
complement activation may be primary event for pregnancy loss
aPLs inhibit production of placental prolactin and insulin growth factor
binding protein-1 thus affecting trophobla. st syncitium formation,
placental apoptosis
14. Other proposed mechanism which may or may
not be dependent on the beta-2 –glycoprotien 1
includes
1. Production of antibodies against
prothrombin,proteinC,S annexins.
2. Activation of platelets to enhance endothelial
adherence.
3. Activation of vascular endothelium—platelet
and monocyte binding.
4. Ab react against oxidized LDL—
atherosclerosis and MI.
15. Clinically the abovementioned mechanism
can affect virtually any organ including :
16. MORTALITY/ MORBIDITY
Increased CVA / MI specially in young pts.
Secondary to valvular vegetations
embolizations or in –situ thrombosis.
Recurrent pulmonary embolism or thrombisis
leads to life htreatening pulm. Htn
Catastrphic APS(CAPS) rare and fatal
manifestaion (50% mortality)– multiorgan
failure in days to weeks.
Late spontaneous fetal loss ( 2nd or 3rd tri)
17. “Sapporo Criteria” (Updated)
International Consensus Statement on
Classification Criteria for APS (2006).
Clinical criteria.
Vascular thrombosis.
Pregnancy morbidity.
Laboratory criteria.
Lupus anticoagulant.
Anticardiolipin IgG or IgM antibody.
Anti-b2glycoprotein I IgG or IgM antibody.
18. Clinical criteria for APS
Vascular thrombosis*.
Venous thromboembolic disease (DVT, PE).
Arterial thromboembolic disease.
Small vessel thrombosis.
* “Coexisting inherited or acquired thrombotic risk
factors are not reasons for excluding patients from a
diagnosis of APS trials.”
19. Clinical criteria for APS
Pregnancy morbidity.
One or more unexplained deaths of a
morphologically normal fetus at or beyond10th
week of gestation.
Three or more unexplained spontaneous abortions
at or prior to 10th week of gestation.
One or more premature births at or before the 34th
week of gestation due to eclampsia or placental
insufficiency.
20. Laboratory criteria for APS
Lupus anticoagulant: defined by a
functional, clot-based assay using the ISTH
guidelines.
Anticardiolipin IgG or IgM antibody.
Anti-b2glycoprotein I IgG or IgM antibody.
--Measured on 2 or more occasions at
least 12 weeks apart.
Lupus anticoagulant test is more specific but less sensitive predictor
than anticardiolipin antibody assys
21.
22. Limitation of revised criteria
Clinical features not included in the criteria but
recognised by the 2006 consencus-
Cardiac valve disese
Livido reticularis
Thrombocytopenia
Nephropathy
Neurologic manifestations
Non criteria lab findings associated with APS
Antibody titre of aCL or anti beta-2-gp1 in the range of 20-40
GPL units
IgA for both antobodies
Antiphosphatidylserine antibodies
Antiprothrombin ab.( asso with haemorrhagic tendency)
23. Thus history of any of the mentioned clinical features should raise
a suspicion-
Thrombosis( DVT/PE ,
MI, TIA or CVA )
especially if reccurrent
and at an early age
Neurologic( migraine,
headache, chorea , seizures,
transverse myelitis)
Unexplained adrenal
insufficiency
History of cardiac murmur
or valvular lesion
Miscarriages ( late
trimester or recurrent)
or premature birth
Hematologic
abnormalities( Hemolytic
anemia or
thrombocytopenia)
24. Risk factors for thrombosis
(two hit hypothesis)
Age >55 in men,>65 in women
Inherited thrombophilias
Oral contraceptives, trauma
Nephrotic syndrome
Malignancy
Immobilization
Surgery
htn,DM2,LDL,↓HDL,cigarette smoking,family h/o
BMI>30kg/m2,microalbuminuria,GFR<60ml/min
27. 2.ARTERIAL THROMBOSIS
Less common
Males, Presence of anti CL ab—risk factor
Present with TIA or stroke (20%),MI(25%)
Gangrene of distal extremeties
Brachial,subclavian arteries (unusual sites)
FUNDUS ( Retinal artery occlusion)
Heart murmur- aortc or mitral insufficiency d/t LIBMANN SACKS
endocarditis
28.
29. 3. CARDIAC disorders
Thrombotic or embolic
Premature athreosclerosis—occlusion
young age with no risk factors for CaVD
Valvular thickening— Aortic , Mitral
Vegetations ----libmann sacks(sterile)
Premature coronary disease
Myocardial infarction
Diffuse cardiomyopathy
Pericardial effusion
In SLE---pericarditis is common
30.
31. 4. Cutaneous
Livedo reticularis
Superficial thrombophlebitis
Leg ulcers
Painful purpura
Splinter Haemorrhages
SNEDDON’s syndrome--- Livido reticularis + stroke +/- aPl
May or may not be associated with APS
34. 4.NEUROLOGICAL disorders
Thrombotic or embolic
LA—independent risk factor for stroke in young
Recurrent strokes—multi infarct dementia
“Chorea --- strongly linked to presence of APL”
Migraine,TM,GBS,ON,ICH,psychosis, cognitive dysfunction.
Mimics multiple sclerosis—cognitive dysfunction
Diff—chorea,migraine,seizure ,dysarthria mc in apl
---ON,bowel ,bladder ,gait—MS
Non enhancing with gadolinium,strongly poisitive ab---APLS
35. 5.obstetrical disorders
Recurrent miscarriages
Fetal demise
Ecclampsia
IUGR
Oligohydramnios
HELLP syndrome
May be the prsenting feature of APLS
MC thrombotic defect leading to fetal demise---15% of miscarriages
36. 7.PULMONARY
Most frequent arterial complication
Antiphospholipid lung syndrome
ARDS, pulm thromboembolism, pulm hypertension.
Diffuse alveolar hemorrhage—non thrombotic manifestation of APS
High mortality
8.ABDOMINAL
Hepatic involvement is common
Acalculous cholecystitis, splenic infarction
Budd chiari syndrome
9.ENDOCRINE
Adrenal insufficiency
Autoimmune thyroidditis
37. 10.RETINAL---CRAO,CRVO,ON,CiRAO
11.HEMATOLOGY-----
thrombocytopenia<1,00,000.
Severe—CAPS,TTP
<50,000—bleeding
12.RENAL
APLN( aPL-associated nephropathy)---renal manifestation of APLS
Thrombosis at any site in renal vasculature.
Thrombotic microangiopathy
Proteinuria with hypocomplementemia.
Malignant hypertension
Flank pain d/t renal artery or vein thrombosis
<10%--ARF—recurrence
38. Catastrophic Antiphospholipid
Syndrome(CAPS)
A syndrome of multisystem involvement .
<1% of patients.
Multiple small vessel occlusions---multi organ failure.
Acute onset
3 different organ systems involve in a week
Acute microangiopathy is characteristic
ARF,ARDS,CEREBRAL INJURY,MYOCARDIAL ischemia.
Potentially lethal
Trigger factors involved---
infections,trauma,neoplasia,pregnancy,lupus flares.
SLE-higher mortality.
39. LAB DIAGNOSIS
IgG and IgM Anticardiolipin and anti beta 2- GP1 antibodies (aCL) by
ELISA.
LA testing (Elongates APTT,Kaolin clotting time,dilute russells viper
venom time(dRVVT )
Repeat the assays after 12 weeks to confirm the diagnosis.
Consider for third test if initial titres were high and strong clinical
suspicion after second test comes negative
Recently—antibodies against annexinV,protein C
Thrombocytopenia is modest(>50000/cumm)
Proteinuria and microscopic hematuria
ESR, Hb, and TLC usually normal (except in acute thrombosis )
40. 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
42. DRVVT
Detection of LA
In vitro test ---ability of venom of russells viper to induce
thrombosis.
In drvvt assay time is set to 23-27 sec
A prolonged clotting time of 30 sec or greater that does not correct
with addition of an equal volume of normal plasma suggests the
presence of LA.
Excess phospholipid is added. Normalised
Both the tests are determined to a ratio.
>1.2---may have.1.6 ---confirm.
More sensitive than APTT for LA
43. What if LA,ACL are negative
If patient experiencing thrombosis or recurrent miscarriages
1. Antibodies to b2 gp1
2. Ab to phosphatidyl serine,ethonalamine,glycerol,inositol
3. AnnexinV
4. Phosphatidyl choline.
44. 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.
Biopsy samples from kidneys demonstrate glomerular and small
arterial microthrombi
45. Differential Diagnosis
Inherited and acquired
thrombophilias
• protein C and protein S deficiency
• factor V Leiden deficiency
• Homocystenemia
• Antithrombin III def
• Prothrombin (G20210A) mutations
Acquired thrombotic defects
• pregnancy and postpartum
• major surgery
• OCP
• Nephrotic syndrome
• Hypertension, DM
• Malignancy
• Infective endocarditis
• Heparin induced tcp
46. Differential of CAPS
TTP( severe cerebral and renal disease)
HUS ( renal failure and hemolysis)
HELLP syndrome*
Sepsis with multiorgan failure and DIC (both
may have raised D-dimer and fdp levels)
PAN and other forms of systemic vasculitis
47. TREATMENT
Asymptomatic individuals in whom blood test findings are positive do
not requires specific treatment.
Primary thrombosis prevention inindividuals who are persistently aPL-positive
lacks an evidence based approach; controlled, prospective, and
randomized studies are in progress.
For secondary thrombosis prevention , the current recommendation is life-long
warfarin, although the necessity, duration, and intensity of warfarin
treatment are still under debate.
Strategies for the prevention of fetal loss in patients who have a prior
history of fetal loss include low-dose aspirin and low molecular weight
heparin (LMWH) for patients fulfilling the Sapporo APS Criteria.
48. In pregnancy---
use heparin and LDA(low dose aspirin)
Heparin also prevents aPL induces complement
activation
Previously prednisolone was used—no benefit as per
trials
IVIG and HCQ may be considered in patients who
failed treatment with heparin.
Warfarin only after organogenesis is complete
(Pauzner et al)
Start prior to conception or at first missed period
Continue for 8-12 weks postpartum an then taper.
Nursing is safe
49.
50.
51. Thrombocytopenia
>50000/cumm----no treatment
< 50000/cumm----Prednisone , IVIG
Aspirin 81mg/day may be given
Enoxaparin-- 0.5mg/kg s.c. once daily
prophylactic and 1 mg/kg s.c. twice daily
therapeutic
Life long anticoagulation as per clinical
studies
52. Alternatives to warfarin
No data indicate the efficacy of warfarin in the treatment of
microangiopathic nephropathy,valvular heart disease, livedo reticularis, or
leg ulcers
Aspirin nd clopidogrel---sec prevention of non cardio embolic strokes
and TIA and recurrence rates almost same as warfarin.
Corticosteroid --- accompanying rheumatic illness
---Severe throbocytopenia
---Hemolytic anemia
---CAPS
For well anticoagulated pts who continue to have thrombosis(but no
definite proven role) -
Hydroxychloroquine (SLE pts)
Statins
IVIG
Plasmapheresis
Recurrence rate is 5-10% with these agents.
53.
54. doses
Warfarin---5-15mg/day qd for 2-5 days INR 2.5-3.5
APTT 2 times baseline----factor Xa assays in case of LA.
aspirin 81mg/day
Hydroxychloroquine—6-7mg/kg/d---200-400mg/d
Cyclophosphamide 2-3 mg/kg/d PO OD,
Steroids—prednisolone 1 mg/kg bw
IV ig---400mg/kg/d iv for 5 days
Statins ---atorva 10mg,pravastatin 40m g,fluvastatin 5 mg
55. New drugs
Rituximab
1000mg iv for 2 doses.seperated by 2 weeks.
Helpful in treating low platelet count, anemia, heart valve disease, skin
ulcers, kidney small vessel clots
TheRITuximab Antiphospholipid Syndrome (RITAPS) Study at HSS is being
undertaken to explore whether the Rituximab is effective against certain aPL-related
clinical problems.
Eculizumab
Role in refractory APS under evaluation
Monoclonal ab, prevents C5 conversion to C5a
Helpful in renal translplant candiddates
Autologous Hematopoietic Stem Cell Transplantation
(HSCT)
Good results have been repor ted with autologous hematopoietic
stem cell transplantation (HSCT) in APS as shown by Statkute et al.
56. FUTURE
More specifically targeted, anti-inflammatory or
immunomodulatory approach in the future.
TNF alpha inhibitors for pregnancy complications
Specific complement inhibitors
Long term outcomes of children born of APS pregnancies
Currently, there is no data to support the primary prevention of
stroke in asymptomatic carriers of aPL.
aPL antibody positive pts with ambiguous events (dizziness,
confusion, visual disturbances)
Alternative effective drug to warfarin.
57. SUMMARY
An autoimmune disease ,acquired, assosciated with heterogenous
antibodies which act through various mechanisms—leading to
thrombosis---diagnosis by sapporo criteria—confirmation on
thrombosis for diagnosis---seperation of lab tests by 12 weeks---
warfarin life long therapy—heparin in pregnancy----CAPS– acute
emergency---INR to be monitored----risk to be explained.---future
trends of target therapy awaited.
58. TAKE HOME MESSAGE
Think of APLS in a young female with thrombosis,fetal wastage and young
male with stroke.
Recurrent migraine headaches in a young female –do APL
INR to be individualized and mainatined at 2.0-3.0
Recurrent –3.0-4.0
LA—DRVVT
IgG ACL –THROMBOSIS
Ig M ACL—HEMOLYTIC ANEMIA
LIVEDO RETICULARIS –THINK OF APLS
CHOREA IN YOUNG –THINK OF APLS
ACL –INCREASES WITH AGE
ACL—ARTERIAL,LA—VENOUS
LIFE LONG ANTICOAGULATION
CAPS—ICU CARE
59. Scholary sources
HARRISON’S PRINCIPLES OF INTERNAL MEDICINE,18th ed
KELLEY’S TEXTBOOK OF RHEUMATOLOGY , 8th ed.
www.emedicine.com
www.lupus.org
www.wikipedia.com
www.lupusawarenessandresearch.com
www.japi.org
www.clinicaltrials.gov