A Case of Antiphospholipid Antibody Syndrome

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  • Other triggers: surgical procedures DIC, rare in APS, more common in catastrophic APS
  • A Case of Antiphospholipid Antibody Syndrome

    1. 1. Physician’s Meet March 17 2010 Dr Jishanth M Prof. Dr A Gowrishankar’s Unit, M4
    2. 2. An Interesting Hypercoagulable State
    3. 3. <ul><li>Manikandan, 19 yr, Male </li></ul><ul><li>Admitted on 26 Dec 2009 </li></ul><ul><li>Presenting Complaints: </li></ul><ul><ul><li>Breathlessness- 1 year </li></ul></ul><ul><ul><li>Fever 1 week </li></ul></ul><ul><ul><li>Pain and discoloration of toes 3days </li></ul></ul><ul><li>H/o Present Illness: </li></ul><ul><ul><li>Breathlessness- Insidious onset, slowly progressive , Gr I-III </li></ul></ul><ul><ul><li>No h/o palpitation/ pedal edema </li></ul></ul><ul><ul><li>H/o fever for last 1 week, high grade continuous fever without chills or rigors </li></ul></ul><ul><ul><li>H/o cough with expectoration +, mucopurulent, non foulsmelling </li></ul></ul><ul><ul><li>H/o Loss of appetite+ with loss of weight </li></ul></ul><ul><ul><li>H/o pain both lower limbs+, R>L, </li></ul></ul><ul><ul><li>with brownish black discoloration of 2 nd & 3 rd toes of R leg </li></ul></ul><ul><ul><li>H/o Cramps +, H/o claudication pain+ </li></ul></ul><ul><ul><li>H/o thinning of both UL&LL + </li></ul></ul><ul><ul><li>No h/o joint pain/swelling/deformities/morning stiffness </li></ul></ul>
    4. 4. <ul><li>Past Medical history: </li></ul><ul><ul><li>Treated for Pulmonary tuberculosis with ATT twice over the past 2 ½ years </li></ul></ul><ul><ul><li>On treatment for breathlessness and cough with expectoration…? Bronchiectasis </li></ul></ul><ul><li>Family History: </li></ul><ul><ul><li>No history of similar illness </li></ul></ul><ul><ul><li>2 nd of non-consanguinous marriage. </li></ul></ul>
    5. 5. <ul><li>On Examination: </li></ul><ul><li>Patient conscious, </li></ul><ul><li>Oriented </li></ul><ul><li>Emaciated </li></ul><ul><li>Pallor+ </li></ul><ul><li>Grade II clubbing + </li></ul><ul><li>Right forefoot gangrene+(2 nd & 3 rd toe) </li></ul><ul><li>Skin of lower limbs dry, scaly and atrophic. </li></ul><ul><li>No rashes </li></ul><ul><li>No deformities of joints </li></ul><ul><li>PR: 70/min, regular </li></ul><ul><li>Absent in R LL(femoral, popliteal, dorsalis pedis and posterior tibial) </li></ul><ul><li>Feeble in L LL </li></ul><ul><li>BP: 130/80 mmHg(RUL) </li></ul>
    6. 6. System Examination: <ul><li>CVS: </li></ul><ul><li> S1S2 heard, P 2 loud </li></ul><ul><li>no murmers </li></ul><ul><li>Abd: </li></ul><ul><li>Soft, no organomegaly </li></ul><ul><li>CNS: </li></ul><ul><li>Higher functions normal </li></ul><ul><li>Generalised wasting of all muscles (UL and LL) </li></ul><ul><li>DTR exaggerated bilaterally </li></ul><ul><li>Plantar B/L flexor </li></ul><ul><li>No meningial signs </li></ul><ul><li>RS: </li></ul><ul><li>Trachea central, </li></ul><ul><li>NVBS+ </li></ul><ul><li>B/L coarse late inspiratory leathery creps + in lower lung fields </li></ul><ul><li>B/lL Rhonchi+ </li></ul>
    7. 9. PROVISIONAL DIAGNOSIS <ul><li>Bronchiectasis </li></ul><ul><li>Old treated tuberculosis </li></ul><ul><li>Gangrene ® 2 nd & 3 rd toe/? Cause </li></ul>
    8. 10. INVESTIGATIONS <ul><li>Hb :10.8 g% </li></ul><ul><li>TC :8400 </li></ul><ul><li>DC :P66L33E1 </li></ul><ul><li>ESR :10/22 </li></ul><ul><li>PCV :30% </li></ul><ul><li>Platelets :1.1L </li></ul><ul><li>MCV :90 fl </li></ul><ul><li>RBS : 102 mg% </li></ul><ul><li>BU :44 mg% </li></ul><ul><li>SCr :1.0 mg% </li></ul><ul><li>Urine Routine </li></ul><ul><li>Alb-nil </li></ul><ul><li>Sugar-nil </li></ul><ul><li>Deposits-1-3 pc/hpf </li></ul><ul><li>ECG: SR/70 per min </li></ul><ul><li>‘ p’ pulmonale + </li></ul>
    9. 11. CXR PA VIEW
    10. 13. Investigation contd… <ul><li>Ultrasound abdomen: </li></ul><ul><li>Liver size and echotexture normal., no cysts </li></ul><ul><li>Kidneys normal, CMD+ </li></ul><ul><li>ECHO: RVH+, Mild PHT, Valves normal, No PE </li></ul><ul><li>Sputum C/s: Pseudomonas s/to cipro; norflox; gentamicin </li></ul><ul><li>Sputum AFB : Negative </li></ul><ul><li>PT : 14.1 s </li></ul><ul><li>INR : 1.0 </li></ul><ul><li>aPTT : 54 s </li></ul>
    11. 14. <ul><li>RA factor: 80 positive </li></ul><ul><li>ASO : 200 positive </li></ul><ul><li>CRP : 96 positive </li></ul><ul><li>ANA : Negative </li></ul><ul><li>Anti dsDNA: Negative </li></ul><ul><li>S Homocysteine : 11.17 </li></ul><ul><li>Anti Phospholipid(aCL) Ig M : 40.30 (N<15) </li></ul><ul><li> IgG : 54.96 (N<15) </li></ul><ul><li>Protein C: 35(normal) </li></ul><ul><li>Protein S: 32( normal) </li></ul>
    12. 15. <ul><li>Started on Inj LMWH s/c BD </li></ul><ul><li>Tab Aspirin 150 mg ½ OD </li></ul><ul><li>Inj Deriphylline IV BD </li></ul><ul><li>Inj Ampicillin 1 g IV TDS </li></ul><ul><li>Changed to Ciprofloxacin 200 mg BD and Gentamicin 80 mg IV BD (Rpt RFT normal) </li></ul>
    13. 16. <ul><li>Vascular Opinion: </li></ul><ul><li>Primary Hypercoagulable state, </li></ul><ul><li>Right Iliac artery occlusion </li></ul><ul><li>Left Temporal artery occlusion </li></ul><ul><li>Continue LMWH </li></ul><ul><li>Sugg: CT Angiogram </li></ul><ul><li>Cardiology opinion </li></ul>
    14. 17. <ul><li>Patient had symptomatic improvement(fever& breathlessnes), but developed R LMN VII N palsy during in hospital stay associated with head ache. </li></ul><ul><li>He was started on Tab Prednisolone 1mg/kg/day </li></ul><ul><li>Patient developed multiple cranial nerve palsy( lower cranial nerves) over next 2 days </li></ul>
    15. 18. <ul><li>Neurophysician Opinion: </li></ul><ul><li>B/L VI, </li></ul><ul><li>R VII, VIII </li></ul><ul><li>B/L IX, X, XI, XII </li></ul><ul><li>Generalised Wasting + </li></ul><ul><li>B/L Brisk reflexes </li></ul><ul><li>Impression: Miliary Tuberculosis with Basal Meningitis; small fibre neuropathy </li></ul>
    16. 19. <ul><li>Chest Physician Opinion: </li></ul><ul><li>?Rheumatoid related ILD with reactivation of Tuberculosis </li></ul><ul><li>Sugg: HRCT, USG Abdomen </li></ul>
    17. 20. CT ANGIOGRAM <ul><li>Short segment stenosis(30-40%) of proximal coeliac artery </li></ul><ul><li>Short segment stenosis(60-70%) of right common iliac artery </li></ul><ul><li>Long segment high-grade stenosis/ occlusion of right distal external iliac artery extenting into common femoral artery </li></ul><ul><li>Occlusion of right popliteal artery with reconstituted flow distally. </li></ul>
    18. 21. <ul><li>VASCULAR REVIEW: </li></ul><ul><li>Sugg: Improve general condition for arterial revascularisation. </li></ul><ul><li>Contnue LMWH </li></ul><ul><li>T Acitrom 4 mg OD </li></ul><ul><li>Monitor PT/INR (2-3) </li></ul>
    19. 22. Further investigations <ul><li>p ANCA: negative </li></ul><ul><li>c ANCA: negative </li></ul><ul><li>HBsAg : negative </li></ul><ul><li>Anti HCV: negative </li></ul><ul><li>HIV (I & II): negative </li></ul>
    20. 23. HRCT Chest
    21. 24. Interlobular septal thickening B/l cystic spaces with peribrochial fibrosis
    22. 25. FINAL DIAGNOSIS <ul><li>?Reactivated CNS tuberculosis with multiple CN palsy </li></ul><ul><li>Secondary Antiphospholipid Syndrome </li></ul><ul><li>Rheumatoid related ILD with bilateral bronchiectasis </li></ul>
    23. 26. Antiphospholipid Syndrome <ul><li>Multisystem autoimmune disease </li></ul><ul><li>Most common acquired thrombophilia </li></ul><ul><li>Described by Hughes (1983) </li></ul><ul><li>A syndrome characterized by the association of: </li></ul><ul><li>thrombosis, obstetric complications and/or thrombocytopenia </li></ul><ul><li>antibodies against phospholipids or against proteins bound to phospholipids . </li></ul>
    24. 27. <ul><li>History </li></ul><ul><ul><li>1906: antiphospholipid antibody discovered in patients with syphilis, complement-fixing antibody that reacted with extracts from bovine hearts </li></ul></ul><ul><ul><li>1952: Conley and Hartmann described circulating anticoagulant in patients with Lupus </li></ul></ul><ul><ul><li>1963: Bowie associated the anticoagulant with thromboembolic events </li></ul></ul><ul><ul><li>1983: First description of syndrome with thrombosis, recurrent miscarriage and thrombocytopenia by Hughes </li></ul></ul><ul><li>Epidemiology </li></ul><ul><ul><li>Most common in young to middle-age adults </li></ul></ul><ul><ul><li>Can occur in children and elderly </li></ul></ul><ul><ul><li>More common in females </li></ul></ul>
    25. 28. <ul><li>TWO TYPES </li></ul><ul><li>Primary </li></ul><ul><li>Secondary - Associated with other autoimmune or rheumatic diseases </li></ul>
    26. 29. Antiphospholipid Syndrome - Etiology <ul><li>Combination of </li></ul><ul><ul><li>genetic background and </li></ul></ul><ul><ul><li>environmental factors: infection, trauma, drugs </li></ul></ul><ul><li>Infections – molecular mimicry with B2GPI </li></ul>
    27. 30. Disease associations
    28. 31. Drug Induced aPLs <ul><li>Mediations reported </li></ul><ul><ul><li>Phenothiazines </li></ul></ul><ul><ul><li>Phenytoin </li></ul></ul><ul><ul><li>Hydralazine </li></ul></ul><ul><ul><li>Procainamide </li></ul></ul><ul><ul><li>Quinidine </li></ul></ul><ul><ul><li>Dilantin </li></ul></ul><ul><ul><li>Ethosuximide </li></ul></ul><ul><ul><li>Alpha-interferon </li></ul></ul><ul><ul><li>Amoxicillin </li></ul></ul><ul><ul><li>Chlorothiazide </li></ul></ul><ul><ul><li>Oral contraceptives </li></ul></ul><ul><ul><li>Propranolol </li></ul></ul><ul><li>Usually transient </li></ul><ul><li>Associated with IgM </li></ul><ul><li>Rarely associated with thrombosis </li></ul><ul><li>Mechanism unknown </li></ul>
    29. 32. Antiphospholipid antibodies <ul><li>Antibodies are directed against phospholipids, plasma proteins bound to phospholipids, or unique antigens revealed during the interaction of the two. </li></ul><ul><li>Antiphospholipid antibodies present in upto 10% of healthy donors </li></ul><ul><li>Incidence increases with age and coexisting chronic disease </li></ul><ul><li>Among patients with thrombosis, prevalence of antiphospholipid antibodies is 4 to 21% </li></ul><ul><li>Increasing risk of thrombosis among those with higher antibody titers </li></ul>
    30. 33. Antiphospholipid Antibodies <ul><li>LA antibodies are directed against plasma proteins bound to anionic phospholipids </li></ul><ul><li>aCL antibodies are directed against phospholipids bound to proteins </li></ul><ul><ul><li>Can be IgA, M, or G (subclasses 1-4) </li></ul></ul><ul><ul><li>IgG (esp G2) associated with a greater risk of APS </li></ul></ul><ul><li>Anti  2 GPI antibodies are directed against a plasma protein that binds phospholipid with high affinity </li></ul><ul><li>Other antibodies of unclear significance: </li></ul><ul><ul><li>prothrombin, annexin V, phosphatidylserine, phosphatidylinositol, phosphatidylcholine </li></ul></ul>
    31. 34. Antiphospholipid Antibodies <ul><li>Lupus Anticoagulant (LA) Antibodies </li></ul><ul><ul><ul><li>Prolonged coagulation in phospholipid-dependent in vitro tests (aPTT, PT, dRVVT) </li></ul></ul></ul><ul><ul><ul><li>Failure to correct with 50:50 mix </li></ul></ul></ul><ul><ul><ul><li>Correction of coagulation time by adding phospholipid </li></ul></ul></ul><ul><ul><ul><li>Higher thrombotic potential than aCL when each are present alone </li></ul></ul></ul><ul><li>Anticardiolipin (aCL) Antibodies </li></ul><ul><ul><ul><li>ELISA assay in the presence of bovine B2GPI </li></ul></ul></ul><ul><li>Anti-Beta 2 Glycoprotein I Antibodies (  2 GPI) </li></ul><ul><ul><ul><li>ELISA assay using human B2GPI coated plates </li></ul></ul></ul><ul><ul><ul><li>most specific </li></ul></ul></ul>
    32. 35. Beta 2 Glycoprotein I <ul><ul><li>Natural inhibitor of coagulation and platelet aggregation </li></ul></ul><ul><ul><ul><ul><li>Inhibits contact activation of coagulation cascade </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inhibits conversion of prothrombin to thrombin </li></ul></ul></ul></ul><ul><ul><li>Most aPL antibodies recognize domain I of b 2 gp </li></ul></ul><ul><ul><li>Binding of antibody increases binding affinity for phospholipids </li></ul></ul>
    33. 36. Significance of aPLs <ul><li>No history of thrombosis and positive aPL: Risk of new thrombosis <1% </li></ul><ul><li>History of thrombosis and positive aPL: Risk of new thrombosis >10% in first year if anticoagulation stopped within 6 months </li></ul>
    34. 37. APS Pathophysiology <ul><li>aPL </li></ul>platelets Coagulation cascade Endothelial cells Activate platelet aggregation Inhibit Protein C, Protein S, thrombomodulin, antithrombin III fibrinolysis TF, adhesion molecules and proinflammatory cytokines Placental tissue Trophoblastic cell growth, apoptosis IL-3 Complement system
    35. 38. APS Pathophysiology
    36. 39. Pathogenesis <ul><li>Activation of platelets </li></ul><ul><li>Activation of vascular endothelium </li></ul><ul><li>Enhanced monocyte expression of Tissue Factor </li></ul><ul><li>Inhibition of Prot C ,Prot S and other coagulation factors </li></ul><ul><li>A/B against other proteins involved in coagulation </li></ul><ul><ul><li>Heparin </li></ul></ul><ul><ul><li>Prothrombin </li></ul></ul><ul><ul><li>Platelet activating factor etc. </li></ul></ul><ul><li>Complement activation </li></ul>
    37. 40. <ul><li>Diagnosis </li></ul><ul><ul><li>At least one antiphospholipid antibody </li></ul></ul><ul><ul><li>At least one clinical manifestation </li></ul></ul>
    38. 41. REVISED SAPPORO CRITERIA, SYDNEY 2006 Clinical Criteria <ul><li>Vascular thrombosis : arterial, venous, or small vessel, in any tissue or organ, confirmed by objective validated criteria </li></ul><ul><li>Pregnancy morbidity : </li></ul><ul><li>- Unexplained fetal death at or beyond 10 weeks gestation </li></ul><ul><li>- Premature birth before 34 weeks gestation because of </li></ul><ul><li>eclampsia, severe pre-eclampsia, or placental insufficiency </li></ul><ul><li>- Three or more consecutive spontaneous abortions before </li></ul><ul><li>10 weeks gestation </li></ul>
    39. 42. Laboratory criteria <ul><li>Lupus anticoagulant , present on at least 2 occasions, at </li></ul><ul><li>least 12 weeks apart </li></ul><ul><li>Anticardiolipin antibodies (ACA), IgG or IgM >30 units for both, present on at least 2 occasions, at least 12 weeks </li></ul><ul><li>apart </li></ul><ul><li>Anti-beta-2-glycoprotein I antibodies (anti-B2GPI), IgG or IgM >20 units for both, present on at least 2 occasions, at least 12 wks apart </li></ul><ul><li>A diagnosis of APS should not be made if a period of greater </li></ul><ul><li>than five years separates the clinical event and positive </li></ul><ul><li>laboratory test. </li></ul>
    40. 43. Clinical Manifestations <ul><li>Vascular thrombosis : arterial and venous </li></ul><ul><li>Skin : Levido reticularis </li></ul><ul><li>Recurrent pregnancy loss </li></ul><ul><li>Neurologic : TIA, stroke, migraine, chorea, seizures, optic neuritis </li></ul><ul><ul><li>SNEDDON SYNDROME : stroke, levido reticularis, hypertension </li></ul></ul><ul><li>Cardiac : Coronary artery disease, premature atherosclerosis, vegetations </li></ul><ul><li>Renal : thrombotic microangiopathy, renal vein thrombosis, renal infarction, renal artery stenosis with hypertension, increased allograft vascular thrombosis, and reduced survival of renal allografts </li></ul><ul><li>Pulmonary : PE, pulmonary hypertension </li></ul><ul><li>GI : Budd-Chiari syndrome, intestinal ischemia and infarction, colonic ulceration, esophageal necrosis and perforation, hepatic infarction, acalculous cholecystitis with gallbladder necrosis, and mesenteric and portal vein thrombosis </li></ul><ul><li>Hematologic : thrombocytopenia, TTP/HUS, hemolytic anemia </li></ul>
    41. 44. Catastrophic APS <ul><li>Multiple, simultaneous vascular occlusions throughout body </li></ul><ul><ul><li>Widespread microthrombi in multiple vascular beds  Massive thromboembolism </li></ul></ul><ul><ul><li>Clinical involvement of at least 3 organ systems over days to weeks </li></ul></ul><ul><ul><li>Histopathologic evidence of occlusions of small and large blood vessels </li></ul></ul><ul><ul><li>Most common organs: kidney>lung>CNS>heart>skin  multiorgan failure </li></ul></ul><ul><ul><li>DIC in 25% </li></ul></ul><ul><ul><li>Respiratory failure, stroke, abnormal liver enzymes, renal insufficiency/failure, adrenal insufficiency, cutaneous infarcts </li></ul></ul><ul><li>Precipitating factor in 55%: Most common is infection </li></ul><ul><li>Usually primary APS </li></ul><ul><li>Mortality > 50% </li></ul>
    42. 45. Treatment-General <ul><li>Anti-thrombotic therapy </li></ul><ul><ul><li>Heparin </li></ul></ul><ul><ul><li>Wafarin </li></ul></ul><ul><li>Pregnancy – controversial </li></ul><ul><ul><li>SC heparin and/or Aspirin </li></ul></ul><ul><li>Immunosuppresion – rarely used </li></ul><ul><li>Treat associated condition eg.SLE </li></ul><ul><li>Risk factor modification eg.smoking , OCP </li></ul>
    43. 46. Anticoagulation <ul><li>Initial therapy – same as those without APS </li></ul><ul><ul><li>Wafarinisation (INR 2-3) </li></ul></ul><ul><li>Recurrent events – greatest benefit with high intensity Wafarin (INR 3-4) with or without aspirin </li></ul>
    44. 47. Treatment-Other <ul><li>Plasmapharesis </li></ul><ul><li>IVIG </li></ul><ul><li>Experimental – fibrinolytics, prostacyclin anti-cytokines </li></ul>
    45. 48. Treatment of Catastrophic APS <ul><li>Treatment </li></ul><ul><ul><li>Treat precipitating factor if present </li></ul></ul><ul><ul><li>Anticoagulation </li></ul></ul><ul><ul><li>Steroids </li></ul></ul><ul><ul><li>IVIG </li></ul></ul><ul><ul><li>Plasma exchange </li></ul></ul><ul><ul><li>Cyclosphosphamide </li></ul></ul><ul><ul><li>Rituximab </li></ul></ul><ul><ul><li>Prostacyclin </li></ul></ul><ul><ul><li>Other fibrinolytics </li></ul></ul>
    46. 49. Future directions of treatment of APS <ul><li>Peptide-specific therapy: peptide with B2GPI epitopes recognized by aPL or B2GPI blocking Ab </li></ul><ul><li>Inhibitors of intracellular signaling triggered by aPL </li></ul><ul><li>Complement activation inhibitors </li></ul><ul><li>Anti-TNF α agents </li></ul><ul><li>Anti CD20 agents </li></ul>
    47. 50. <ul><li>Primary prophylaxis…????? </li></ul>
    48. 51. Summary <ul><li>APS – under-recognized autoimmune disease that accounts for a significant proportion of thromboembolic disease and recurrent pregnancy loss </li></ul><ul><li>The etiology and pathophysiology involves aPL as “first hit” and environmental factors, including infection as “secondary hit” </li></ul><ul><li>APS - complex disorder with evolving diagnostic criteria </li></ul><ul><li>Anticuagulation rather than immunosuppresion is the current mainstay of therapy </li></ul><ul><li>Well-designed prospective studies are required to complete the understanding of the optimal treatment. </li></ul>
    49. 52. Uniqueness of the case under discussion….
    50. 53. ….THANK YOU….

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