This document discusses anti-phospholipid syndrome (APS), also known as Hughes syndrome. APS is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies. The key points covered include: 1. APS criteria requiring one clinical (thrombosis, pregnancy loss) and one laboratory (lupus anticoagulant, anticardiolipin, anti-beta 2 glycoprotein I antibodies) feature. 2. Treatment involves anticoagulation with heparin and long-term warfarin, with target INRs of 2.0-3.0 for venous thrombosis and 3.0 for arterial thrombosis. 3

1. Anti Phospho-Lipid Antibody
(APLA) Syndrome (APS)

2. Other names
Multiple terms for APS exist. Some confusing.
• Hughes syndrome
• Anticardiolipin Syndrome (ACL)
• Anti- Phospho Lipid Antibody (APLA) syndrome

3. Other names
Multiple terms for APS exist. Some confusing.
• Lupus anticoagulant (LA) syndrome: Misleading
term because
– patients with APS may not have SLE, and
– LA is associated with thrombotic rather than
hemorrhagic complications.

4. Other names
Multiple terms for APS exist. Some confusing.
• Lupus anticoagulant (LA) syndrome: Misleading
term because
– Patients with APS may not have SLE, and
– LA is associated with thrombotic rather than
hemorrhagic complications.

5. Anti-phospholipid syndrome (APS)
Is a disorder that manifests as-
• Recurrent venous or arterial thrombosis and/or
• Complications of pregnancy (fetal losses) +
• Characteristic lab abnormalities.

6. Anti-phospholipid syndrome (APS)
APS is currently the preferred term.
Previous Classification-
• Primary - no associated disease,
• Secondary- in association with SLE /other
rheumatic (AI) disorders
Current classification -
1. APS with, or
2. APS without associated rheumatic disease.

7. Anti-phospholipid syndrome (APS)
APS is currently the preferred term.
Previous Classification-
• Primary - no associated disease,
• Secondary- in association with SLE /other
rheumatic (AI) disorders
Current classification -
1. APS with, or
2. APS without associated rheumatic disease.

8. Antiphospholipid syndrome (APS)
Although antiphospholipid (aPL) abs are linked to
APS, their role in pathogenesis (cause or an
epiphenomenon) is unclear.
Up to 5% of healthy people have aPL abs.

9. APS
• It is a heterogenous disorder in terms of
clinical manifestations and range of
autoantibodies.
• In 2006, revised criteria for the diagnosis of
APS were published in an international
consensus statement.
• At least one clinical criterion and one
laboratory criterion must be present for a
patient to be classified as having APS.

10. Antiphospholipid Syndrome Criteria
Sydney revision of Sapporo criteria 2006
CLINICAL CRITERIA
1. Vascular Thrombosis
2. Pregnancy Morbidity:
a) death of normal fetus
at > 10 wks
b) premature birth at < 34
wks due to preeclampsia
c) >3 consecutive abortions
at <10wks
d) placental insufficiency at
< 34 wks
LAB CRITERA
1. anti-Cardiolipin IgG / IgM
2. anti–beta-2 glycoprotein I
(GP1)
3. Lupus anticoagulant
(LAC)
- medium to - high titer
- at least X 2 times
- 12 wks apart

11. Antiphospholipid Syndrome Criteria
Sydney revision of Sapporo criteria 2006
CLINICAL CRITERIA
1. Vascular Thrombosis
2. Pregnancy Morbidity:
a) death of normal fetus
at > 10 wks
b) premature birth at < 34
wks due to preeclampsia
c) >3 consecutive abortions
at <10wks
d) placental insufficiency at
< 34 wks
LAB CRITERA
1. anti-Cardiolipin IgG / IgM
2. anti–beta-2 glycoprotein I
(GP1)
3. Lupus anticoagulant
(LAC)
- medium to - high titer
- at least X 2 times
- 12 wks apart
Definite APS: 1 Clinical + 1 Lab criteria

12. APS: The clinical criteria are-
1. Vascular thrombosis
–One or more clinical episodes of arterial,
venous, or small-vessel thrombosis
–In any tissue or organ
–Thrombosis may involve (cerebral, coronary,
pulmonary, limb, hepatic, renal, ocular or
adrenal) any circulation.
–Confirmed by imaging, doppler, or histopath
studies

13. APS: The clinical criteria are-
1. Vascular thrombosis
Inv is warranted if DVT/ PE/ acute ischemia/ MI/
CVA (esp. recurrent) is present
in a young individual in the absence of other risk
factors.

14. The clinical criteria are-
2. Pregnancy morbidity
–One or more late-term (>10 wks) spontaneous
abortions
–One or more premature births of a
morphologically healthy neonate at /before 34
wks due to pre/eclampsia or severe placental
insufficiency
–Three or more unexplained, consecutive,
spontaneous abortions before 10 wks
gestation

15. Laboratory criteria:
Patients must have raised
1. IgG or IgM anticardiolipin (aCL), or
2. anti–beta-2 glycoprotein I (GP1), or
3. Lupus anticoagulant (LA)
On
• at least 2 occasions
• at least 12 weeks apart

16. Additionally..
• Other antiphospholipid (aPL)–associated clinical
features recognized by the 2006 consensus
statement but not included in the criteria are-
• Cardiac valve disease
• Livedo reticularis
• Thrombocytopenia
• Nephropathy, and
• Neurologic manifestations

19. Suspect APLA syndrome if…
• Thrombosis
• Miscarriage
• Heart murmur or cardiac valvular vegetations
• Hematologic abnormalities (TCP or HA)
• Nephropathy
• Non-thrombotic neurologic symptoms
• Unexplained adrenal insufficiency
• Avascular necrosis of bone
• Pulmonary hypertension

20. Suspect APLA syndrome if…
• Thrombosis
• Miscarriage
• heart murmur or cardiac valvular vegetations
• hematologic abnormalities (TCP or HA)
• nephropathy
• Non-thrombotic neurologic symptoms,
• Unexplained adrenal insufficiency
• Avascular necrosis of bone
• Pulmonary hypertension
- in the absence of other risk factors

21. APLA Syndrome - Etiology
APS is an autoimmune disorder of unknown cause.
Possible triggers are-
• Associated autoimmune or rheumatic diseases
• Infections and
• Drugs associated with the LA or aCL antibodies.

22. APLA Syndrome -Etiology
Asso diseases Infections Drugs Others
SLE Syphilis Cardiac- Procainamide,
quinidine, propranolol,
hydralazine
Familial
association
Sjogrens HCV Neuroleptic /psychiatric -
Phenytoin, chlorpromazine
HLA
associations:
between aCL
ab and indivs
with certain
HLA genes
RA HIV Other - Interferon alfa,
quinine, amoxicillinAI TCP HTLV I
AI HA Malaria
Psoriatic
arthropathy
Bacterial
septicemia
PSS
MCTD
PMR/ GCA

23. Differential Diagnosis
• DIC
• IE
• TTP
• Acquired prothrombotic disorders

24. Acquired prothrombotic disorders
• Conditions associated with a hypercoagulable
state:
- Pregnancy and postpartum
- major surgery
- Obesity and immobility
- malignancy
- Congestive heart failure
- Nephrotic syndrome
• Estrogen treatment
• Antiphospholipid syndrome
-

25. APS: Laboratory Studies
The hallmark that defines antiphospholipid
syndrome (APS) is
• The presence of antiphospholipid (APL)
antibodies or
• Abnormalities in phospholipid-dependent tests of
coagulation.

26. APS: Laboratory Studies
The hallmark that defines antiphospholipid
syndrome (APS) is
• The presence of antiphospholipid (APL)
antibodies or
• Abnormalities in phospholipid-dependent tests of
coagulation.

27. APS: Laboratory Studies
The hallmark that defines antiphospholipid
syndrome (APS) is
• The presence of antiphospholipid (APL)
antibodies or
• Abnormalities in phospholipid-dependent tests of
coagulation.

28. APS: Laboratory Studies
• In addition to the clinical criteria listed, at least
one of the following laboratory criteria is
necessary for the classification of APS:

29. APS: Laboratory Studies
• Presence of LA in plasma on 2 or more occasions
at least 12 weeks apart
• Presence of moderate to high levels of
anticardiolipin (aCL) (IgG or IgM) in serum/
plasma (ie, >40 IgG phospholipid units (GPL)/mL or
IgM phospholipid units (MPL)/mL or >99th
percentile) on 2 or more occasions at least 12
weeks apart

30. APS: Laboratory Studies
• Presence of moderate to high levels of
anti–beta-2 glycoprotein I antibodies (IgG or
IgM) in serum or plasma (>99th percentile) on 2 or
more occasions at least 12 weeks apart
• Presence of LA in plasma on 2 or more occasions
at least 12 weeks apart

31. APS: Laboratory Studies
LA is directed against plasma coagulation molecules.
• Results in the paradoxical prolongation of clotting assays,
such as aPTT, kaolin clotting time, and dilute Russell viper
venom time (DRVVT).
• The presence of LA is confirmed by mixing normal
aCL antibodies react primarily to membrane
phospholipids
• platelet-poor plasma with the patient's plasma.
• If a clotting factor is deficient, the addition of normal
plasma corrects the prolonged clotting time.
• If the clotting time does not normalize during mixing
studies, an inhibitor is present; the absence of a specific
clotting factor inhibitor confirms that a LA is present.

32. APS: Laboratory Studies
LA is directed against plasma coagulation
molecules.
• Results in the paradoxical prolongation of
clotting assays, (such as aPTT, kaolin clotting
time, and dilute Russell viper venom time
(DRVVT)).

33. APS: Laboratory Studies
LA is directed against plasma coagulation
molecules.
• Results in the paradoxical prolongation of
clotting assays, such as aPTT, kaolin clotting time,
and dilute Russell viper venom time (DRVVT).
• The presence of LA is confirmed by mixing
normal platelet-poor plasma with the patient's
plasma.
If

34. APS: Laboratory Studies
• If a clotting factor is deficient, the addition of
normal platelet poor plasma corrects the
prolonged clotting time.
• If the clotting time does not normalize during
mixing studies, an inhibitor is present; the
absence of a specific clotting factor inhibitor
confirms that a LA is present.

35. APS: Laboratory Studies
• aCL antibodies react primarily to membrane
phospholipids

36. APS: Summary of Laboratory Studies
Following laboratory tests should be done:
• aCL antibodies (IgG, IgM)
• Anti–beta-2 glycoprotein I antibodies (IgG, IgM)
• Activated partial thromboplastin time (aPTT)
• LA tests such as DRVVT
• Serologic test for syphilis (false-positive result)
• CBC count (thrombocytopenia, hemolytic
anemia)
• A low ANA level may be present and does not
necessarily imply coexisting SLE.

37. False Positives
• Infections:
- 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

38. APS Treatment: Thrombosis
• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.
• Based on the most recent evidence, a reasonable
target for the INR is
–Venous thrombosis -2.0-3.0
–Arterial thrombosis 3.0
– Recurrent thrombotic events -may require 3.0-4.0
– Severe or refractory cases- combination of warfarin+
aspirin maybe used.
• Treatment is generally lifelong.

39. APS Treatment: Thrombosis
• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.
• Based on the most recent evidence, a reasonable
target for the INR is
– Venous thrombosis -2.0-3.0
– Arterial thrombosis 3.0
– Recurrent thrombotic events -may require 3.0-4.0
• Severe or refractory cases- combination of
warfarin+ aspirin maybe used.
• Treatment is generally lifelong.

40. APS Treatment: Thrombosis
• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.
• Based on the most recent evidence, a reasonable
target for the INR is
– Venous thrombosis -2.0-3.0
– Arterial thrombosis 3.0
– Recurrent thrombotic events -may require 3.0-4.0
• Severe or refractory cases- combination of
warfarin+ aspirin maybe used.
• Treatment is generally lifelong.

41. APS Treatment: Thrombosis
• Full anticoagulation with IV/ SC heparin followed
by warfarin therapy.
• Based on the most recent evidence, a reasonable
target for the INR is
–Venous thrombosis -2.0-3.0
–Arterial thrombosis 3.0
– Recurrent thrombotic events -may require 3.0-4.0
• Severe or refractory cases- combination of
warfarin+ aspirin maybe used.
• Treatment is generally lifelong.

42. APS Treatment: Obstetric considerations
Guidelines available-
• Heparin safe in pregnancy, preferred LMWH.
• Warfarin contraindicated in pregnancy.
• Heparin and warfarin safe in breast feeding.
• No history of thrombosis -Prophylaxis
• History of thrombosis -Full anticoagulation

43. APS Treatment: Obstetric considerations
Guidelines available-
• History of thrombosis -Full anticoagulation
– Prophylactic SC heparin (LMWH) + low-dose
aspirin during pregnancy.
– Rx withheld at delivery. Restarted after, continued
for 6-12 wks postpartum.
– Long-term anticoagulation then continued
postpartum.

44. APS Treatment: Obstetric considerations
Guidelines available-
• History of thrombosis -Full anticoagulation
• Corticosteroids -not been proven effective.
Increase maternal morbidity and fetal
prematurity rates.

45. Prophylactic therapy
• Eliminate other risk factors, such as oral
contraceptives, smoking, hypertension, or
hyperlipidemia.
• Low-dose aspirin; the effectiveness as primary
prevention for APS remains unproven.
• Clopidogrel anecdotal reports (aspirin allergy).
• In SLE, consider hydroxychloroquine, for intrinsic
antithrombotic properties.
• Statins, esp for hyperlipidemia.

46. Catastrophic Antiphospholipid
Syndrome (CAPS)
• Catastrophic antiphospholipid syndrome is
rare, affecting < 1% of those with
antiphospholipid syndrome.
• Also called Asherson's syndrome after the
researcher who described it in 1990s.
• These patients are generally very ill, often
with active SLE.
• There is widespread thrombosis in several
vascular beds

47. Catastrophic Antiphospholipid
Syndrome (CAPS)
Treatment
• Intensive anticoagulation
• Plasma exchange
• Corticosteroids appears beneficial
No controlled trials have been performed.
• IV Ig -some benefit
• Cyclophosphamide in selected cases (SLE-
associated CAPS).

48. Take Home Messages:
Anti- Phospholipid Syndrome
• Due to the wide spectrum of manifestations any
clinician may encounter patients with APS
• This is a potentially treatable condition
• The best treatment, at present to prevent
recurrent thrombosis is anticoagulation.
• The optimal duration and intensity is
controversial.

49. THM: Venous or Arterial thrombosis
1. Initial treatment with Heparin
2. Start Warfarin
3. Stop Heparin when therapeutic INR achieved

50. Current Recommendations
• Asymptomatic aPL no treatment (Aspirin?)
• Venous thrombosis Warfarin INR 2.0-3.0
• Arterial thrombosis Warfarin INR 3.0
• Recurrent thrombosis Warfarin INR 3.0-4.0
+ Aspirin
• CAPS Anticoagulation + CS
+ IVIg or plasmapheresis

51. Potentially usable
• Non-aspirin antiplatelet agents
• Hydroxychloroquine
• Statins
• Thrombin inhibitors
• Rituximab
• Recombinant activated protein C
• Prostaglandin and prostacyclin
• Anti-cytokine

52. Thrombocytopenia
• Mild to moderate- Platelets > 50,000:
No treatment
• Severe- <50,000: corticosteroids
• Corticosteroid resistant cases:
HCQ
IVIG,
Immunosuppressive drugs,
Splenectomy

53. 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

54. Other Rx for APL Ass 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

55. Take Home Messages:
Anti- Phospholipid Syndrome
• Due to the wide spectrum of manifestations any
clinician may encounter patients with APS
• This is a potentially treatable condition
• The best treatment, at present to prevent
recurrent thrombosis is anticoagulation.
• The optimal duration and intensity is
controversial.