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Antiphospholipid syndrome



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Antiphospholipid syndrome

  2. 2. INTRODUCTION THROMBOSIS IS HEMOSTASIS IN WRONG PLACE  Antiphospholid syndrome(APS) is an autoimmune disorder which manifests clinically as recurrent arterial or venous thrombosis and/or fetal loss.  Characteristic lab abnormality exists as antibodies directed against membrane anionic phospholipids( anticardiolipin antibody,antiphosphatidylserine) or their assocaited plasma protiens (beta 2 glycoprotein I).
  3. 3.  Also known as  HUGHES SYNDROME named after Graham Hughes.  Antiphospholipid antibody syndrome  LUPUS ANTI COAGULANT SYNDROME (misnomer)  Mostly assosciated with SLE.  Responsible for frequent miscarriages in young females (15%).
  4. 4. 1. Primary antiphospholipid syndrome APS occurs in the absence of any other related disease. 2. Secondary antiphospholipid syndrome APS occuring in the context of other autoimmune diseases, such as systemic lupus erythematosus (SLE). 3. Catastrophic antiphospholipid syndrome In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed (CAPS) and is associated with a high risk of death.
  5. 5. EPIDEMIOLOGY  In healthy people---frequency of aPL antibodies is 1-5 %  Prevalence ↑ with age ,in elderly with chronic disease.  Risk of thrombosis is 0.5-30%  SEX-Women :men is 5:1  AGE- Young and middle age adults  RACE- African american and Hispanics  Females---arthritis,livedo,migraine  Males—MI,epilepsy,lower extremity arterial thrombosis  Apl ab—30-40% in SLE---10% have APLS  aPL syndrome is the cause of  14 % of all strokes  11 % of all MI  10% of DVT  6% of pregnancy morbidity  9% of pregnancy lossses
  6. 6. Etiology  Although aPL antibodies are clinically linked to APS whether they are invoved in pathogenesis is unclear  Possible triggers identified  Infections (via molecular mimicry)  Syphilis  Hepatitis C infection  HIV  Malaria  Bacterial septicemia  Drugs- Procainamide, Quinidine, propranolol, hydralazine, phenytoin, chlorpromazine, quinine  Genetic predisposition- HLA –DRW53,DR7—HISPANIC DR4 - white.
  7. 7. Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies" : 1.anticardiolipin antibodies (ACA) 2. lupus anticoagulant(LA) 3. Anti beta-2 glycoprotien 1 antibodies They may be b2 gp1 dependent (aotuimmune aPLs) or independent(infection and drug induced aPLs) The presence of aPL, may be demonstrated directly by: •Serum assays (ELISA)--- anticardiolipin antibody(ACA) and -----anti beta2-glycoprotein (GP) I antibody •Clotting assay ----- effects of an aPL on the phospholipid-dependent factors in the coagulation cascade (lupus anticoagulant [LA] test)
  8. 8. pathology
  9. 9. PATHOPHYSIOLOGY  The family of APL ab are heterogenous and the targets vary.  Under physiologic conditions B2GPI act as elimination of apoptotic cells and as natural anticoagulant.  There are distinct clinical ,laboratory and biochemical differences between the disorders mediated by the different antibodies. ACL---risk of stroke—arterial thrombosis LA---venous thrombosis TNF alpha and complement activation –pregnancy loss
  10. 10. Activation or defective apoptosis of platelets, endothelial cells or trophoblasts Phosphatidylserine or cardiolipin( negatively charged phospholipid) migrates to outer cell surface Circulating B2Gp1 bind to phosphhatidylserine aPL antibodies bind to B2 Gp1 dimer Activation of complement(C5a) and release of cytokines(TNF alpha) via migration of inflammatory cells produces a prothrombotic state
  11. 11. pathogenesis
  12. 12. Homeostatic regulation of blood coagulation is altered.  Defect in cellular apoptosis---exposure of membrane phospholipids to the binding of various plasma proteins---b2gp1 complex, neoepitope---target for autoantibodies.  Oxidized b2GP1---activates dendritic cells –autoantibodies are produced.  Emerging evidence from animal studies suggest that aPLmediate complement activation may be primary event for pregnancy loss  aPLs inhibit production of placental prolactin and insulin growth factor binding protein-1 thus affecting trophobla. st syncitium formation, placental apoptosis
  13. 13. In pregnancy
  14. 14.  Other proposed mechanism which may or may not be dependent on the beta-2 –glycoprotien 1 includes 1. Production of antibodies against prothrombin,proteinC,S annexins. 2. Activation of platelets to enhance endothelial adherence. 3. Activation of vascular endothelium—platelet and monocyte binding. 4. Ab react against oxidized LDL— atherosclerosis and MI.
  15. 15.  Clinically the abovementioned mechanism can affect virtually any organ including :
  16. 16. MORTALITY/ MORBIDITY  Increased CVA / MI specially in young pts.  Secondary to valvular vegetations embolizations or in –situ thrombosis.  Recurrent pulmonary embolism or thrombisis leads to life htreatening pulm. Htn  Catastrphic APS(CAPS) rare and fatal manifestaion (50% mortality)– multiorgan failure in days to weeks.  Late spontaneous fetal loss ( 2nd or 3rd tri)
  17. 17. “Sapporo Criteria” (Updated)  International Consensus Statement on Classification Criteria for APS (2006).  Clinical criteria.  Vascular thrombosis.  Pregnancy morbidity.  Laboratory criteria.  Lupus anticoagulant.  Anticardiolipin IgG or IgM antibody.  Anti-b2glycoprotein I IgG or IgM antibody.
  18. 18. Clinical criteria for APS  Vascular thrombosis*.  Venous thromboembolic disease (DVT, PE).  Arterial thromboembolic disease.  Small vessel thrombosis. * “Coexisting inherited or acquired thrombotic risk factors are not reasons for excluding patients from a diagnosis of APS trials.”
  19. 19. Clinical criteria for APS  Pregnancy morbidity.  One or more unexplained deaths of a morphologically normal fetus at or beyond10th week of gestation.  Three or more unexplained spontaneous abortions at or prior to 10th week of gestation.  One or more premature births at or before the 34th week of gestation due to eclampsia or placental insufficiency.
  20. 20. Laboratory criteria for APS  Lupus anticoagulant: defined by a functional, clot-based assay using the ISTH guidelines.  Anticardiolipin IgG or IgM antibody.  Anti-b2glycoprotein I IgG or IgM antibody. --Measured on 2 or more occasions at least 12 weeks apart. Lupus anticoagulant test is more specific but less sensitive predictor than anticardiolipin antibody assys
  21. 21. Limitation of revised criteria  Clinical features not included in the criteria but recognised by the 2006 consencus-  Cardiac valve disese  Livido reticularis  Thrombocytopenia  Nephropathy  Neurologic manifestations  Non criteria lab findings associated with APS  Antibody titre of aCL or anti beta-2-gp1 in the range of 20-40 GPL units  IgA for both antobodies  Antiphosphatidylserine antibodies  Antiprothrombin ab.( asso with haemorrhagic tendency)
  22. 22. Thus history of any of the mentioned clinical features should raise a suspicion- Thrombosis( DVT/PE , MI, TIA or CVA ) especially if reccurrent and at an early age Neurologic( migraine, headache, chorea , seizures, transverse myelitis) Unexplained adrenal insufficiency History of cardiac murmur or valvular lesion Miscarriages ( late trimester or recurrent) or premature birth Hematologic abnormalities( Hemolytic anemia or thrombocytopenia)
  23. 23. Risk factors for thrombosis (two hit hypothesis)  Age >55 in men,>65 in women  Inherited thrombophilias  Oral contraceptives, trauma  Nephrotic syndrome  Malignancy  Immobilization  Surgery  htn,DM2,LDL,↓HDL,cigarette smoking,family h/o  BMI>30kg/m2,microalbuminuria,GFR<60ml/min
  24. 24. CLINICAL FEATURES(SPECTRUM) Clinical features varies from asymptomatc aPL positivity to catastrophic APS  1.VENOUS THROMBOSIS  Lower extremities, DVT  Ascites (Budd chiari syndrome)  Tachypnea (PE)  Abnormal fundoscopic examination (Retinal vein thrombosis)  >50% have asymptomatic pulmonary embolism  Unusual anatomic locations (Cerebral veins, superior saggital sinus, Budd Chiari syndrome, upper limb thrombosis)
  25. 25. Retinal vein thrombosis
  26. 26.  2.ARTERIAL THROMBOSIS  Less common  Males, Presence of anti CL ab—risk factor  Present with TIA or stroke (20%),MI(25%)  Gangrene of distal extremeties  Brachial,subclavian arteries (unusual sites)  FUNDUS ( Retinal artery occlusion)  Heart murmur- aortc or mitral insufficiency d/t LIBMANN SACKS endocarditis
  27. 27.  3. CARDIAC disorders  Thrombotic or embolic  Premature athreosclerosis—occlusion  young age with no risk factors for CaVD  Valvular thickening— Aortic , Mitral  Vegetations ----libmann sacks(sterile)  Premature coronary disease  Myocardial infarction  Diffuse cardiomyopathy  Pericardial effusion  In SLE---pericarditis is common
  28. 28.  4. Cutaneous  Livedo reticularis  Superficial thrombophlebitis  Leg ulcers  Painful purpura  Splinter Haemorrhages SNEDDON’s syndrome--- Livido reticularis + stroke +/- aPl May or may not be associated with APS
  29. 29. Livedo reticularis
  30. 30. Splinter hemorrhages
  31. 31. 4.NEUROLOGICAL disorders  Thrombotic or embolic  LA—independent risk factor for stroke in young  Recurrent strokes—multi infarct dementia  “Chorea --- strongly linked to presence of APL”  Migraine,TM,GBS,ON,ICH,psychosis, cognitive dysfunction.  Mimics multiple sclerosis—cognitive dysfunction  Diff—chorea,migraine,seizure ,dysarthria mc in apl  ---ON,bowel ,bladder ,gait—MS  Non enhancing with gadolinium,strongly poisitive ab---APLS
  32. 32.  5.obstetrical disorders  Recurrent miscarriages  Fetal demise  Ecclampsia  IUGR  Oligohydramnios  HELLP syndrome  May be the prsenting feature of APLS  MC thrombotic defect leading to fetal demise---15% of miscarriages
  33. 33. 7.PULMONARY  Most frequent arterial complication  Antiphospholipid lung syndrome  ARDS, pulm thromboembolism, pulm hypertension.  Diffuse alveolar hemorrhage—non thrombotic manifestation of APS  High mortality 8.ABDOMINAL  Hepatic involvement is common  Acalculous cholecystitis, splenic infarction  Budd chiari syndrome 9.ENDOCRINE  Adrenal insufficiency  Autoimmune thyroidditis
  34. 34. 10.RETINAL---CRAO,CRVO,ON,CiRAO 11.HEMATOLOGY-----  thrombocytopenia<1,00,000.  Severe—CAPS,TTP  <50,000—bleeding 12.RENAL  APLN( aPL-associated nephropathy)---renal manifestation of APLS  Thrombosis at any site in renal vasculature.  Thrombotic microangiopathy  Proteinuria with hypocomplementemia.  Malignant hypertension  Flank pain d/t renal artery or vein thrombosis  <10%--ARF—recurrence
  35. 35. Catastrophic Antiphospholipid Syndrome(CAPS)  A syndrome of multisystem involvement .  <1% of patients.  Multiple small vessel occlusions---multi organ failure.  Acute onset  3 different organ systems involve in a week  Acute microangiopathy is characteristic  ARF,ARDS,CEREBRAL INJURY,MYOCARDIAL ischemia.  Potentially lethal  Trigger factors involved--- infections,trauma,neoplasia,pregnancy,lupus flares.  SLE-higher mortality.
  36. 36. LAB DIAGNOSIS  IgG and IgM Anticardiolipin and anti beta 2- GP1 antibodies (aCL) by ELISA.  LA testing (Elongates APTT,Kaolin clotting time,dilute russells viper venom time(dRVVT )  Repeat the assays after 12 weeks to confirm the diagnosis.  Consider for third test if initial titres were high and strong clinical suspicion after second test comes negative  Recently—antibodies against annexinV,protein C  Thrombocytopenia is modest(>50000/cumm)  Proteinuria and microscopic hematuria  ESR, Hb, and TLC usually normal (except in acute thrombosis )
  37. 37. Tests for LAC No LAC shows 100% specificity and sensitivity because aPLs are heterogeneous. More than 1 test system is needed  APTT: - variability in reagents result in inconsistent sensitivity. - acute phase reaction and pregnancy may shorten APTT and mask a weak LAC A normal APTT does not exclude LAC  KCT- Kaolin clotting time more sensitive to presence of anti-II  DRVVT- Dilute Russell’s viper venom time more sensitive to presence of b2 GPI  TTI - Tissue thromboplastin inhibition test
  38. 38. Diluted Russells viper venom test
  39. 39. DRVVT  Detection of LA  In vitro test ---ability of venom of russells viper to induce thrombosis.  In drvvt assay time is set to 23-27 sec  A prolonged clotting time of 30 sec or greater that does not correct with addition of an equal volume of normal plasma suggests the presence of LA.  Excess phospholipid is added. Normalised  Both the tests are determined to a ratio.  >1.2---may have.1.6 ---confirm.  More sensitive than APTT for LA
  40. 40. What if LA,ACL are negative  If patient experiencing thrombosis or recurrent miscarriages 1. Antibodies to b2 gp1 2. Ab to phosphatidyl serine,ethonalamine,glycerol,inositol 3. AnnexinV 4. Phosphatidyl choline.
  41. 41. Imaging studies  For confirmation  USG  COLOR DOPPLER  CT SCAN  MRI  2D ECHO  Histology----non inflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic vasculitis.  Biopsy samples from kidneys demonstrate glomerular and small arterial microthrombi
  42. 42. Differential Diagnosis Inherited and acquired thrombophilias • protein C and protein S deficiency • factor V Leiden deficiency • Homocystenemia • Antithrombin III def • Prothrombin (G20210A) mutations Acquired thrombotic defects • pregnancy and postpartum • major surgery • OCP • Nephrotic syndrome • Hypertension, DM • Malignancy • Infective endocarditis • Heparin induced tcp
  43. 43. Differential of CAPS  TTP( severe cerebral and renal disease)  HUS ( renal failure and hemolysis)  HELLP syndrome*  Sepsis with multiorgan failure and DIC (both may have raised D-dimer and fdp levels)  PAN and other forms of systemic vasculitis
  44. 44. TREATMENT  Asymptomatic individuals in whom blood test findings are positive do not requires specific treatment.  Primary thrombosis prevention inindividuals who are persistently aPL-positive lacks an evidence based approach; controlled, prospective, and randomized studies are in progress.  For secondary thrombosis prevention , the current recommendation is life-long warfarin, although the necessity, duration, and intensity of warfarin treatment are still under debate.  Strategies for the prevention of fetal loss in patients who have a prior history of fetal loss include low-dose aspirin and low molecular weight heparin (LMWH) for patients fulfilling the Sapporo APS Criteria.
  45. 45. In pregnancy---  use heparin and LDA(low dose aspirin)  Heparin also prevents aPL induces complement activation  Previously prednisolone was used—no benefit as per trials  IVIG and HCQ may be considered in patients who failed treatment with heparin.  Warfarin only after organogenesis is complete (Pauzner et al)  Start prior to conception or at first missed period  Continue for 8-12 weks postpartum an then taper.  Nursing is safe
  46. 46.  Thrombocytopenia  >50000/cumm----no treatment  < 50000/cumm----Prednisone , IVIG  Aspirin 81mg/day may be given  Enoxaparin-- 0.5mg/kg s.c. once daily prophylactic and 1 mg/kg s.c. twice daily therapeutic  Life long anticoagulation as per clinical studies
  47. 47. Alternatives to warfarin  No data indicate the efficacy of warfarin in the treatment of microangiopathic nephropathy,valvular heart disease, livedo reticularis, or leg ulcers  Aspirin nd clopidogrel---sec prevention of non cardio embolic strokes and TIA and recurrence rates almost same as warfarin.  Corticosteroid --- accompanying rheumatic illness ---Severe throbocytopenia ---Hemolytic anemia ---CAPS  For well anticoagulated pts who continue to have thrombosis(but no definite proven role) -  Hydroxychloroquine (SLE pts)  Statins  IVIG  Plasmapheresis  Recurrence rate is 5-10% with these agents.
  48. 48. doses  Warfarin---5-15mg/day qd for 2-5 days INR 2.5-3.5  APTT 2 times baseline----factor Xa assays in case of LA.  aspirin 81mg/day  Hydroxychloroquine—6-7mg/kg/d---200-400mg/d  Cyclophosphamide 2-3 mg/kg/d PO OD,  Steroids—prednisolone 1 mg/kg bw  IV ig---400mg/kg/d iv for 5 days  Statins ---atorva 10mg,pravastatin 40m g,fluvastatin 5 mg
  49. 49. New drugs  Rituximab  1000mg iv for 2 doses.seperated by 2 weeks.  Helpful in treating low platelet count, anemia, heart valve disease, skin ulcers, kidney small vessel clots  TheRITuximab Antiphospholipid Syndrome (RITAPS) Study at HSS is being undertaken to explore whether the Rituximab is effective against certain aPL-related clinical problems.  Eculizumab  Role in refractory APS under evaluation  Monoclonal ab, prevents C5 conversion to C5a  Helpful in renal translplant candiddates  Autologous Hematopoietic Stem Cell Transplantation (HSCT)  Good results have been repor ted with autologous hematopoietic stem cell transplantation (HSCT) in APS as shown by Statkute et al.
  50. 50. FUTURE  More specifically targeted, anti-inflammatory or immunomodulatory approach in the future.  TNF alpha inhibitors for pregnancy complications  Specific complement inhibitors  Long term outcomes of children born of APS pregnancies  Currently, there is no data to support the primary prevention of stroke in asymptomatic carriers of aPL.  aPL antibody positive pts with ambiguous events (dizziness, confusion, visual disturbances)  Alternative effective drug to warfarin.
  51. 51. SUMMARY  An autoimmune disease ,acquired, assosciated with heterogenous antibodies which act through various mechanisms—leading to thrombosis---diagnosis by sapporo criteria—confirmation on thrombosis for diagnosis---seperation of lab tests by 12 weeks--- warfarin life long therapy—heparin in pregnancy----CAPS– acute emergency---INR to be monitored----risk to be explained.---future trends of target therapy awaited.
  52. 52. TAKE HOME MESSAGE  Think of APLS in a young female with thrombosis,fetal wastage and young male with stroke.  Recurrent migraine headaches in a young female –do APL  INR to be individualized and mainatined at 2.0-3.0  Recurrent –3.0-4.0  LA—DRVVT  IgG ACL –THROMBOSIS  Ig M ACL—HEMOLYTIC ANEMIA  LIVEDO RETICULARIS –THINK OF APLS  CHOREA IN YOUNG –THINK OF APLS  ACL –INCREASES WITH AGE  ACL—ARTERIAL,LA—VENOUS  LIFE LONG ANTICOAGULATION  CAPS—ICU CARE
  53. 53. Scholary sources  HARRISON’S PRINCIPLES OF INTERNAL MEDICINE,18th ed  KELLEY’S TEXTBOOK OF RHEUMATOLOGY , 8th ed.      