1. Antiphospholipid symdrome “APS”

2. Definition
Disorder of recurrent vascular thrombosis, pregnancy loss and thrombocytopenia associated with persistently raised levels of anti-phospholipid antibodies.
Primary: Occurs alone
Secondary: Associated with other autoimmune or rheumatic diseases

3. Epidemiology of APLs Prevalance : Unknown Women : 60-80 %
Familial disease : Frequent
HLA-DQB

4. Antiphospholipid Antibodies
Common finding
significant proportion of healthy (esp. elderly) population
most never thrombosis
may be transient

5. Antiphospholipid Antibodies
Clinically significant antiphospholipid antibodies are not antiphospholipid antibodies
Antibodies against phospholipid-bound proteins
e.g. b2 glycoprotein 1, prothrombin

6. Anti-Phospholipid antibodies
Lupus Anti-coagulant
Anti-cardiolipin antibody
Anti-ß2 glycoprotein I antibody
Anti-prothrombin
False + serologic test for Syphillis

7. Antiphospholipid syndrome
Association of a thrombotic tendency
venous or arterial thrombosis
recurrent miscarriages
with the persistence of one or more antiphospholipid antibodies
confirmed by two different tests, or IgG or IgM by ELISA(LA,ACL)
repeated after 6 week

8. Lupus Anti-coagulant Blocks In Vitro assembly of prothrombinase
Prolongs
aPTT
dRVVT(Russell viper venum time )
KPC(Kaolin clotting )

9. Anti-cardiolipin antibody
React with phospholipids such as cardiolipin
Different immunoglobulin subclasses and isotypes are associated with anti-cardiolipin antibodies
IgG, IgA, IgM (IgG 1-4)
Increased levels of IgG acl incurs a greater risk of thrombosis
85% concordance LA and ACL

10. Anti-ß2 glycoprotein I antibody
Inhibitor of coagulation (phospholipid binded)
Occurs alone in 11%
Also known Apolipoprotein H
Phospholipid bound inhibitor of coagulation and platelet aggregation
Inhibits contact activation of clotting
Inhibits Prothrombin to Thrombin conversion
Found in large percentage of primary and secondary APS

11. False + serologic test for Syphillis
Phospholipid dependant tests
Syphillis antigen-cardiolipin

12. Anti-prothrombin Associated with higher risk of recurrent thrombosis
Risk independent of presence of ACL or LA

13. Pathogenesis

14. Mechanism of thrombosis
Antiphospholipid Ab :
Interference in cells of coagulation
Selective inhibition of protein C anticoagulant pathway

15. Interference in cells of coagulation
Antiphospholipid Ab activation
Endothelial cell
Monocyte
Inducing :
Adhesion molecule,
Tissue Factor
Endothelin
TX A2
Antiplatelet Ab
Expression : TF
TXA2
Platelet activation
Aggregation vasoconstriction
Thrombosis

16. Mechanism of fetal loss
Antiphospholipid Ab
Direct effect on throphoblast
Endothelial cell lesion of placental vessels
Competes with Annexin
Intraplacental thrombosis
Tissue hypoxia
Fetal loss

17. Clinical manifestation

18. Disease associations

19. Clinical manifestation
Major :
Vascular thrombosis
Pregnancy morbidity
Minor :
Hematologic :Thrombocytopenia,…
Dermatologic : ( Livedo reticularis….)
Neurologic : ( CVA ….)
Others

20. Vascular thrombosis Sporadic In < 50 years
Unrelated to antibody level
Recurrent
Venous : Deep vein thrombosis of the leg
Arterial : Stroke
Small vessel : Kidneys & Skin

21. Pregnancy morbidity Unexplained fetal death
Unexplained spontaneous abortion
Premature birth before the 34th weeks of gestation
Others : Fetal distress , preclampsia , post partum thrombotic accident , HELLP syndrome , fetal growth disorder

22. Hematologic APL a/b in 70-82% of SLE and thrombocytopenia
Mild to moderate(100,000 – 150,000 )
APL a/b in 70-82% of SLE and thrombocytopenia
30 – 40% with ITP
ITP therefore may be associated with thrombosis
Hemolytic anemia :
Positive combs test

23. Dermatologic Raynoud phenomen Livedo reticularis
Superficial thrombophelebitis
Leg ulcer
Cutaneous necrosis
Splinter hemorrhage
Acrocyanosis

24. Livedo reticularis

25. Livedo reticularis with necrotic finger tips in Antiphospholipid syndrome

26. Neurologic Migraine headache Stroke & TIA Chorea Memory loss Dementia
Multiple sclerosis-like syndrome
Transverse myelitis
Seizure
Non focal neurologic symptoms
Guillene-barre

27. Others Libman-sacks endocarditis Valvular insufficiency
Pulmonary hypertension
Renal failure

28. Laboratory tests

29. Laboratory tests
Anti cardiolipin ( ACL ) & Lupus anti coagulant ( LA ) test : for people suspected of having APS
Anti B2GP1 : for people with signs of APS but normal ACL & LA tests
Platelet , ANA , ESR , Urinalysis : for patient with SLE

30. Drug induced APLa

31. Drug induced APS
Phenytoin , Hydralazine , Chlorpromazine , Procainamide
IgM isotype of antiphospholipid Ab
Antiphospholipid no related to B2GP1
Thrombosis and Thrombocytopenia

32. DIAGNOSIS

33. Diagnosis
Definite APS is considered to be persist if at least one of the clinical and one of the laboratory criteria are presented

34. Vascular thrombosis :
One or more clinical episode of arterial , venous or small-vessel thrombosis in any tissue or organ and
Thrombosis confirmed by imaging or Doppler studies or histopathology , with the exception of superficial venous thrombosis
Histopathologic confirmation with thrombosis in the absence of inflammation in the vessel wall

35. Pregnancy morbidity
Unexplained fetal death : After the 10th weeks of gestation (one or more)
Unexplained spontaneous abortion : before the 10th weeks of gestation (3 or more)
Premature birth before the 34th weeks of gestation (one or more)

36. Laboratory criteria ACL Ab L.A Ab IgG and/or IgM isotype in blood
Medium or high titer on two or more occasions at least six weeks apart
Measured by standard ELISA for B2GP1 dependent
L.A Ab
Present in plasma on two or more occasions at least six weeks apart,

37. Diseases association

38. Disease associations Long list of associated diseases Main Groups SLE
Autoimmune
Infections and drugs
Neoplasms
Genetic
Other

40. Non-Autoimmune causes for positive Antiphosphospholipid Ab tests
Assay Antibody type Causes
ELISA B2GP1 independent Syphlis,lyme
Leptospirosis, HIV
B2GP1 dependent Advanced age
Drug
Lymphoproliferative
Hyperimmunoglobulin M
LA Either HIV , Drugs

41. Catastrophic APS

42. Catastrophic vascular occulsion syndrome
Multiple vascular of medium and small arteries that occurring over a period of day
Risk factors : Infection, Drugs, Small surgery, Anticoagulant withdrawal, Post partum period
Often history of SLE or PAPS
Stroke , Cardiac , Hepatic , Adrenal , Renal and Intestinal infarction , Peripheral gangrene , Thrombocytopenia , Hemolytic anemia , Hypertension
Biopsy : Non-inflammatory vascular occlusion
50% mortality

43. Treatment

44. Treatment-General Thrombotic therapy Pregnancy – controversial
Heparin
Wafarin
Pregnancy – controversial
SC heparin and/or Aspirin
Immunosuppresion – rarely used
Treat associated condition eg.SLE
Risk factor modification eg.smoking , OCP

45. APS treatment Asymptomatic Positive antiphospholipid Ab : no treatment
Venous thrombosis :
Peripheral venous thrombosis : INR = 2
Proximal thrombosis , Budd-chiari syndrome , Cavernous or sagittal sinus thrombosis , Pulmonary emboli : INR =3
Arterial Thrombosis : INR = 3

46. APS treatment
First pregnancy, Single pregnancy loss < 10th week : Low dose Aspirin
Recurrent fetal loss , loss after 10th week : Heparin 5000 U bid throughout pregnancy Discontinue 6-12 weeks postpartum
Recurrent fetal loss , loss after 10th week +Thrombosis : Heparin 5000 U bid throughout pregnancy and Warfarin postpartum

47. Treatment-Other Plasmapharesis IVIG
Experimental – fibrinolytics, prostacyclin anti-cytokines

48. Treatment - CAPS
Uncontrolled data to suggest intensive treatment betters outcome(70% recovery)
Anticoagulation
Steroids
Plasmapharesis or IVIG
Treatment of any precipitant eg. Infection
Cytotoxics (if indicated eg.Active SLE )