Antiphospholipid syndrome (APS) is an acquired autoimmune condition characterized by arterial or venous thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies. The document discusses the history, incidence, definition, classification, clinical manifestations, diagnostic criteria, treatment and management of APS. APS can affect multiple organ systems and present with a wide variety of clinical symptoms. Prompt diagnosis and treatment with anticoagulation and immunosuppression is important to prevent morbidity and mortality.

1. ANTI PHOSPHOLIPID SYNDROME (APS )
Dr.A.P.Naveen Kumar
Chief Specialist (Gen. Med. )
Visakhapatnam Steel Plant

2. 04/06/13
HISTORY
• Unusual clotting inhibitor in SLE- 1952
• BFP-STS - false positive test for syphilis
• 1976- Johannsen – recurrent thrombi
• Nelson et al first reported with recurrent abortions
• 1984 – concept of APS

3. 04/06/13
• Substances in the blood, called phospholipids, are required
for the blood to clot.
• In some people, the body mistakenly identifies
phospholipids, or proteins bound to the phospholipids, as
foreign substances and forms antibodies against them.
•
• This reaction can be viewed as a confusion of the immune
system, called an autoimmune process
• Certain substances, such as phospholipids, must also be
present in the blood for the clotting proteins to function
properly and form a clot.

4. 04/06/13
INCIDENCE
• 1-5% of general population have positive APLA
• 10% of DVT and PE
• 12 – 34 % of LUPUS
• Typically are not inherited but acquired

5. 04/06/13
DEFINITION
APS is the commonest acquired prothrombotic state and
it is associated with one or more of the
antiphospholipid antibodies namely
• anti cardiolipin antibody ( ACLA),
• Lupus anticoagulant ( LA ) or
• anti β2 glycoprotein 1 antibody
Plus
One of the clinical manifestations namely arterial
thrombosis, venous thrombosis and recurrent foetal
loss. Thrombocytopenia and autoimmune hemolytic
anemia are also strong clinical associations.

6. 04/06/13
CLASSIFICATION
• Primary
• Secondary
• SLE – other CVD
• Auto immune hypothyroidism
• Infections
• Drugs

7. 04/06/13
• Secondary APS is classified as Autoimmune and
Alloimmune
• Alloimmune are usually transient and not
associated with clinical complications
• Infections are alloimmune
• Drugs maybe allo or autoimmune

8. 04/06/13
INFECTIONS
• HIV
• TB
• Syphilis
• Lyme disease
• Infectious Mononucleosis
• Hep. C

9. 04/06/13
DRUGS
• Phenothiazines
• Procainamide
• Chlorpromazine
• Hydralazine
• Phenytoin
• Valproate

10. 04/06/13
Sapporo criteria ( 8th International
Symposium on APA ,Sapporo-Japan )
• The Sapporo criteria for definite APS are the
presence of at least one of the listed clinical
criteria and at least one of the two listed
laboratory criteria.
• Two clinical criteria include vascular thrombosis
and pregnancy morbidity

11. • Vascular thrombosis consists of one or more
04/06/13
clinical episodes of arterial, venous or small
vessel thrombosis in any tissue or organ.
• The thrombosis must be confirmed by imaging or
doppler or histopathology with the exception of
superficial venous thrombosis.
• If HPE is performed there should be thrombosis
with no significant e/o inflammation in the vessel
wall

12. • Three categories of pregnancy morbidity
04/06/13
Category –A
• consists of one or more unexplained deaths of a
morphologically normal foetus at or beyond the
10 th week of gestation.
• Ultrasound or direct examination of the foetus
must document normal fetal morphology

13. 04/06/13
Category –B
• consists of one or more premature births of a
morphologically normal neonate at or before the
34 th week of gestation due to severe pre-
eclampsia or eclampsia, or severe placental
insufficiency

14. 04/06/13
Category –C
• Consists of three or more unexplained
consecutive spontaneous abortions before the
10th week of gestation ,following exclusion of
both maternal anatomic or hormonal
abnormalities and paternal and maternal
chromosomal abnormalities

15. 04/06/13
• According to a 2006 consensus statement,(Sydney-2006 ) it
is advisable to classify APS into one of the following
categories for research purposes:
• I: more than one laboratory criterion present in any
combination;
• IIa: lupus anticoagulant present alone
• IIb: anti-cardiolipin IgG and/or IgM present alone in
medium or high titers
• IIc: anti-β2 glycoprotein I IgG and/or IgM present alone in
a titer greater than 99th percentile

16. 04/06/13
LABORATORY CRITERIA
• Anticardiolipin antibody of the Ig G or Ig M type
present in medium or high titre on 2 or more
occasions 6 weeks apart
• Lupus anticoagulant present in plasma on 2 or
more occasions at least 6 weeks apart detected
by aPTT , KCT (kaolin clotting time ) ,dilute
Russell’s viper venom time (DRVVT ),dilute
prothrombin time (PT )

17. 04/06/13
• ACLA is 6 times more common than LA
• 80 % of APA have ACLA
• 20% have LA only
• Both are positive in 60%
• Anti β2GP1 assay in SLE patients is useful

18. 04/06/13

19. • 20 yr. girl-hypothyroid and
anemic, past h/o ATT
• Presented with convulsions
• MRI brain – large bleed
• Thrombocytopenia

20. • Persistant headache
• Drowsy and not
improving
• MR Venogram – Sup.
Saggital sinus
thrombosis
• LMWH given
• APLA workup positive

21. CNS 04/06/13
• Stroke in young
Singh K, Shome DK et al - 18.8 %
• Sneddon ‘s syndrome – livedo reticularis ,stroke and CVA
• Non thrombotic neurologic symptoms like focal neurologic
manifestations
• Multiple hyperintense lesions in a MRI in young ind. < 40
• Siezures
• CSVT , Multi infarct dementia , migraine headache,GB
Syndrome ,chorea and optic neuritis

22. 04/06/13
• 24 yr. old boy –hematuria and
rt. Loin pain
• u/s abd. Grossly enlarged rt.
Kidney –carcinoma
• CT abd. –renal vein thrombosis
• Investigations – N
• Hypercoagulable states workup
done

23. 04/06/13
RENAL
• Severe HTN, proteinuria ,hematuria ,nephrotic
syndrome ,ESRD and renal failure
• Post transplant renal thrombosis
• Renal artery stenosis ,malignant HTN,renal
infarction, renal vein thrombosis ,thrombotic
microangiopathy and glomerulonephritis

24. 04/06/13
CARDIAC
• Myocardial infarctions ,premature and
accelerated atherosclerosis
• Valve thickening , regurgitation , stenosis and
vegetations
• Valvular abnormalities – 30-50%
• MR - 25% , AR – 6-10 %
• Recurrent re-stenosis

25. 04/06/13
PULMONARY
• Lung syndrome –
pulmonary microthrombosis, PTE , PAH, ARDS
intra alveolar hemorrhage and postpartum
syndrome

26. • 22 yr. old girl
• Polyarthritis and rash
• Gangrene of tips of fingers
• Treated with LMWH and then
acitrom
• Recovered completely
• ANA , DsDNA , Anti Cardiolipin
positive
• On follow up

27. • 35 yr. female
• Fever , rash and polyarthritis
• Gangrene of fingers and toes
• Started on steroids , LMWH and
HCQS
• Workup for SLE and APA was
positive
• Acitrom started steroids tapered
off

28. 04/06/13
SKIN
• Livedo reticularis
• Digital gangrene
• Subungal splinter hemorrhages
• Superficial venous thrombosis
• Thrombocytopenic purpura
• Pseudovasculitic manifestations
• Generalised vasculopathy

29. • 28 yr. female
• Recurrent abortions
• Anti cardiolipin antibodies positive
• Started on anticoagulants
• Delivered a female baby with LMWH

30. 04/06/13
OBSTETRIC
• Spontaneous miscarriages
• Maternal thrombocytopenia
• Placental insufficiency
• Annexin -5 markedly reduced

31. • 15 yr. boy asymptomatic earlier
• Presented with fever and abdominal pain
• Developed blurring of vision ,headache and altered
sensorium
• MRI –bilateral cortical hemorrhages
• Thrombocytopenia and hypokalemia
• Went into septicemia and MODS -ventilated
• Recovered completely with steroids except for
thrombocytopenia
• ANA positive – treated with steroids
• After 1 yr. developed swelling of abdomen
• U/S s/o Budd Chiari
• Investigations confirmed APLA

33. 04/06/13
GIT
• Budd-chiari syndrome
• Intestinal ischemia and infarction
• Colonic ulceration
• Esophageal necrosis and perforation
• Hepatic infarction
• Mesentric and portal vein thrombosis

34. • 12 yr. girl
• Recurrent abdominal pain
• Confirmed as pancreatitis
• Later symptoms of rash and arthritis
• Investigations for SLE and APLA pos
• On immunomodulants and acitrom
• Developed CNS lupus and recovered

35. • 34 yr. female
• Polyarthritis and skin rash
• Developed swelling of leg
• Doppler showed DVT
• ANA,DsDNA,Smith and Anti cardiolipin Ab.
positive

36. ACA SYNDROME

37. 04/06/13
OTHERS
• Autoimmune sensorineural hearing loss
• Bleeding complications secondary to acquired
hypo prothrombinemia –venous end occlusion
by thrombus can lead to capillary bleeding

38. 04/06/13
CLINICAL TYPES
• Type –1 Retinal / CNS / Major organs
• Type - 2 Arterial
• Type - 3 Venous
• Type - 4 Arterial and venous
• Type - 5 Obstetrical
• Type - 6 Asymptomatic antibody positivity

39. 04/06/13
MALIGNANCY ASSOCIATION
• B cell Lymphoma
• CML
• NHL
• Renal cell carcinoma
• Lung adenocarcinoma
• Breast carcinoma
• Melanoma

40. CATASTROPHIC APS
04/06/13
• Serious form of APS with MOD
• Histopathological e/o multiple occlusions of large or small
vessels
• Kidney ,lung ,CNS ,heart,adrenal and skin are involved usually
in that order
• Gut maybe involved resulting in gut ischemia and abd. pain
• Thrombotic storm - multiple microemboli
• Precipit. factors are infections , surgical procedures and drugs
• Very high mortality

41. 04/06/13
VASCULITIS AND APS
• Strong association between vasculitis and
thrombosis and the cause effect relationship is
not clear
• Vasculitis has been reported as a complication of
APS itself

42. 04/06/13
DD
• Factor V Leiden mutation
• Hyperhomocystenemia
• Classic PAN
• Infective endocarditis
• Cholesterol embolism
• TTP
• Infections

43. PRIMARY PROPHYLAXIS
04/06/13
• Low dose aspirin is the first logical option
• Physician Health Study did not show any protection in men
• HCQS -protective against thrombosis in SLE pts. with APLA
• Aspirin with low intensity warfarin therapy under study in UK
• Treatment of HTN,DM,DLD and stop smoking
• Prophylaxis with heparin in high risk conditions

44. TREATMENT 04/06/13
• Anticoagulation -INR between 3-4
• INR - 2-3 – venous thrombosis
• INR – 3-4 - recurrent thrombosis and arterial
thrombosis
• Recent trials suggest that a INR of 2-3 is as good for the
prevention of future thrombosis
• HCQS – 200-400 mgs.
• Role of steroids and immunosuppressives is ?
• Definite role in Lupus and APA
• Steroids in catastrophic APS and repeated thrombosis

45. 04/06/13
PREGNANCY AND APS
• For pregnancy loss low dose aspirin plus heparin
• IVIG – in women with pregnancy loss despite treatment
with aspirin and heparin
• Planned pregnancy – stop warfarin before conception and
start heparin to prevent warfarin embryopathy
• Continue heparin both antepartum and postpartum until
warfarin is re introduced
• Monitor fetal growth and uteroplacental blood flow
• Timely delivery

46. 04/06/13
• Recommendations suggest lifelong anticoagulation
• One study showed abnormal d dimer test one month after
discontinuation of anticoagulation can be used as an
indicator for continuation of anticoagulation
• Study – 223 /608 (36.7% ) test was positive
• 18 events in 120 pts. who stopped (15%)
• 3 events in 103 pts. who resumed (2.9%)
• Study concluded that pts, with abnormal D dimer
level at 1 month after discontinuation have a
significant incidence of thrombosis,which is
reduced by resumption of anti coagulation
(NEJM- 2006 –Cosmi ,Legani et al )

47. TREATING OTHER
04/06/13
COMPLICATIONS
• Thrombocytopenia - Steroids is the choice,
danazol ,dapsone ,HCQS, Splenectomy
• Headache – aspirin ,warfarin
• Heart valve lesions – replacement
• ESRD – Transplant – prognosis not good

48. COMMON CLUES
04/06/13
• Cerebrovascular accidents
• Myocardial infarction
• Pulmonary thromboembolism
• DVT
• Recurrent foetal loss
• Non healing ulcer
• Livedo reticularis
WITHOUT ANY KNOWN RISK FACTOR

49. 04/06/13
Recognize the condition
early,at the same time
avoiding overdiagnosing this
condition, as the treatment
in unwarranted situations
can be hazardous

50. 04/06/13
Sensitizing the physician’s mind for
diagnosis of APS is important , especially
because of its varied manifestations and
because, it is treatable on the other hand
it can lead to significant morbidity,
disability and mortality if left untreated.

51. 04/06/13
THANK YOU

52. 04/06/13

53. 04/06/13

54. 04/06/13

55. 04/06/13