ANTIPHOSPHOLIPID ANTIBODY SYNDROME By Dr. Arvind Mishra M.D.

1. ANTIPHOSPHOLIPID ANTIBODY SYNDROME By Dr. ArvindMishraM.D. Professor Department of Internal Medicine

2. LECTURE AND MCQs

3. ANTIPH0SPHOLIPID ANTIBODY SYNDROME Antiphospholipid antibody syndrome is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis and/or pregnancy morbidity in the presence of autoantibodies against phospholipid (PL)-binding plasma proteins.

4. Classification and Nomenclature of Antiphospholipid Antibodies 1)Antibodies against cardiolipin (aCL), a negatively charged phospholipid, detected by enzyme-linked immunosorbent assay (ELISA).

5. 2)Antibodies against apolipoproteinβ- 2 Glycoprotein I (antiβ-2GPI) detected by ELISA in the absence of PL.

6. 3)Lupus Anticoagulant detected by clotting assays. LA constitutes a heterogeneous group of antibodies directed also against PL binding proteins, mainly β-2GPI and prothrombin.

7. LA antibodies induce elongation in vitro of the following clotting times: • Activated partial thromboplastin time (aPTT) • Kaolin clotting time (KCT) • Dilute Russel viper venom test (dRVVT)

8. Antibodies against phospholipids/cholesterol complexesdetected as biologic false-positive serologic test for syphilis (BFP-STS) and Venereal Disease Research Laboratory Test (VDRL).

9. EPIDEMIOLOGY • occur in 1–5% of general population • Systemic lupus erythematosus (SLE)(1/3rd cases) • Systemic sclerosis (scleroderma) • Sjögren's syndrome • Dermatomyositis • Rheumatoid arthritis

10. PATHOGENESIS- • Preceding infections as initiating event • Anti phospholipid antibodies 1)inactivate natural anticoagulants such as protein C(Activated protein C (APC) binds the pro-coagulant factors Va and VIIIa and inactivates them) 2)activate cells involved in the coagulation cascade to a prothrombotic phenotype

11. 3) activate complement 4)activate nuclear factor kappa B (NF-kB) in monocytes and endothelial cells leading to the secretion of pro-inflammatory cytokines, ; the expression of adhesion molecules and ; and the expressions of tissue factor, changing the phenotype of these cells to a prothrombotic form

12. MANIFESTATIONS Venous Thrombosis and Related Consequences % Deep vein thrombosis 39 Livedoreticularis 24 Pulmonary embolism 14 Superficial thrombophlebitis 12

13. Arterial Thrombosis % Stroke 20 Cardiac involvement 14 Transient ischemic attack 11 Leg ulcers and/or digital gangrene 9 Arterial thrombosis in the extremities 7 Retinal artery thrombosis 7 Ischemia of visceral organs 6

14. NEUROLOGIC MANIFESTATIONS 1)Migraine 20% 2)Epilepsy 7% 3)Chorea 1% 4)Cerebellar Ataxia 1% 5)Transverse Myelopathy 0.5%

15. RENAL MANIFESTATIONS 1)Renal artery thrombosis 2)Renal vein thrombosis 3)Fibrous intimal hyperplasia

16. OSTEOARTICULAR MANIFESTATIONS 1)Arthralgia 39% 2)Arthritis 27% OBSTETRIC MANIFESTATIONS 1)Preeclampsia 10% 2)Eclampsia 4%

17. FETAL MANIFESTATIONS 1)Early fetal losses(<10 weeks) 35% 2)Late fetal losses(>10 weeks) 17% 3)Premature birth 11% HEMATOLOGICAL MANIFESTATIONS 1)Thrombocytopenia 30% 2)Autoimmune hemolytic anemia 10%

18. DIAGNOSIS Presence of at least one clinical and one laboratory criteria CLINICAL CRITERIA 1)Vascular thrombosis defined as one or more episodes of arterial, venous or small vessel thrombosis in any tissue or organ 2)Pregnancy morbidity defined as; a)One or more unexplained death of a morphologically normal fetus at or beyond the 10th week of gestation.

19. b)One or more premature births of a morphologically normal neonate before 34th week of gestation because of eclampsia ,preeclampsia,or placental insufficiency. c)Three or more unexplained consecutive spontaneous abortions before 10th week of gestation. LABORATORY CRITERIA 1)Lupus anticoagulant 2)Anticardiolipin antibody 3)Anti –β 2GPI antibody at intermediate or high titres on two occasions,12 weeks apart.

20. DIFFERENTIAL DIAGNOSIS 1)Inherited or acquired causes of thrombophilia 2)Coombs positive hemolytic anemia 3)Livedoreticulariscan be seen in a)Polyarteritisnodosa b)Cryoglobulinemia c)Lymphomas d)Myeloproliferative disorders e) Atherosclerosis

21. TREATMENT a)Anticoagulants i.e. warfarin and aspirin for life long to maintain INR b/w 2.5 to 3.5 if patient developedthrombotic event. b)In Pregnancy combination of heparin and aspirin. c)80 mg aspirin daily in antiphospholipid antibody positive patients to prevent thrombotic events.

22. If recurrent thrombotic events despite adequate anticoagulation; 1)IVIG 400 mg/kg qd for 5 days 2)Anti-CD 20 monoclonal antibody 375 mg/m2 per week for 4 weeks

23. MCQs

24. 1)All are true regarding lupus anticoagulant except a)Thrombocytosis b)Increased abortions c)Rashes d)Arterial thrombosis

25. Ans .a

26. 2)Isolated prolongation of APTT with bleeding caused by all except a)Factor VIII Deficiency b)Factor IX Deficiency c)Factor XI Deficiency d) Presence of Lupus anticoagulant

27. Ans .d

28. 3)A 25 year old lady presented with history of recurrent abortions.The most relevant investigation to identify the cause is a)Bleeding time b)Prothrombin time c)Dilute russel viper venom time d)Thrombin time

29. Ans .c

30. 4)Treatment of choice in a pregnant women with positive test for antiphospholipid antibodies a)Aspirin only b)Aspirin +low molecular weight heparin c)Aspirin +warfarin d)Rituximab/IVIG

31. Ans .b

32. 5)True about lupus anticoagulant include all except a)Life threatening bleeding episodes b)Increased aPTT c)May occur without clinical signs d)Recurrent mid trimester abortions

33. Ans .a

34. 6)Most common hematological manifestation of Antiphospholipid antibody syndrome is a)Anemia b)Leucopenia c)Thrombocytopenia d)a+b

35. Ans .c