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Anti phospholipid syndrome

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Immunology, Hematology

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Anti phospholipid syndrome

  1. 1. Anti Phospho-Lipid Antibody (APLA) Syndrome (APS)
  2. 2. Other names Multiple terms for APS exist. Some confusing. • Hughes syndrome • Anticardiolipin Syndrome (ACL) • Anti- Phospho Lipid Antibody (APLA) syndrome
  3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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.
  20. 20. 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
  21. 21. Differential Diagnosis • DIC • IE • TTP • Acquired prothrombotic disorders
  22. 22. 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 -
  23. 23. 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.
  24. 24. 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.
  25. 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. 26. 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:
  27. 27. 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
  28. 28. 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
  29. 29. 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.
  30. 30. 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)).
  31. 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 platelet-poor plasma with the patient's plasma. If
  32. 32. 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.
  33. 33. APS: Laboratory Studies • aCL antibodies react primarily to membrane phospholipids
  34. 34. 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.
  35. 35. 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
  36. 36. 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.
  37. 37. 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.
  38. 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. 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. 40. 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
  41. 41. 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.
  42. 42. APS Treatment: Obstetric considerations Guidelines available- • History of thrombosis -Full anticoagulation • Corticosteroids -not been proven effective. Increase maternal morbidity and fetal prematurity rates.
  43. 43. 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.
  44. 44. 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
  45. 45. 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).
  46. 46. 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.
  47. 47. THM: Venous or Arterial thrombosis 1. Initial treatment with Heparin 2. Start Warfarin 3. Stop Heparin when therapeutic INR achieved
  48. 48. 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
  49. 49. Potentially usable • Non-aspirin antiplatelet agents • Hydroxychloroquine • Statins • Thrombin inhibitors • Rituximab • Recombinant activated protein C • Prostaglandin and prostacyclin • Anti-cytokine
  50. 50. Thrombocytopenia • Mild to moderate- Platelets > 50,000: No treatment • Severe- <50,000: corticosteroids • Corticosteroid resistant cases: HCQ IVIG, Immunosuppressive drugs, Splenectomy
  51. 51. 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
  52. 52. 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
  53. 53. 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.

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