ANTIPHOSPHOLIPID SYNDROME

1. ANTIPHOSPHOLIPID
SYNDROME
(APS)
Dr Saurabh Gupta
PG medicine
VMMC AND SJH

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)

8. pathology

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

11. pathogenesis

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

13. In pregnancy

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

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

25. CLINICAL FEATURES(SPECTRUM)
Clinical features varies from asymptomatc aPL positivity to catastrophic APS
 1.VENOUS THROMBOSIS
 Lower extremities, DVT
 Ascites (Budd chiari syndrome)
 Tachypnea (PE)
 Abnormal fundoscopic examination (Retinal vein thrombosis)
 >50% have asymptomatic pulmonary embolism
 Unusual anatomic locations (Cerebral veins, superior saggital sinus, Budd Chiari
syndrome, upper limb thrombosis)

26. Retinal vein thrombosis

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

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

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

32. Livedo reticularis

33. Splinter hemorrhages

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

41. Diluted Russells viper venom 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

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.

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