Antiphospholipid antibody syndrome

APS recent guidelines on diagnosis and management

1. ANTIPHOSPHOLIPID ANTIBODY SYNDROME Ajay Kumar Yadav 2075/05/15 PGY3,Medicine

2. LAYOUT Introduction Historical background Classification criteria for APS Types of APS Clinical presentations Management

3. INTRODUCTION The antiphospholipid syndrome ( APS )is a systemic autoimmune disease defined by thrombotic or obstetrical events that occur in patients with persistent antiphospholipid antibodies(APLA) Thrombosis may be venous , arterial or microvascular . The deep veins of the lower extremities and the cerebral circulation are the most common sites of venous and arterial thrombosis respectively. Obstetrical APLA is characterized by fetal loss after 10th week of gestation, recurrent early miscarriages, intrauterine growth restriction, or severe preeclampsia. A definite diagnosis of APS requires the presence of at least 1 clinical and 1 laboratory criterion. The term APS is not synonymous with APLA.

4. When do we suspect APS? Clinical suspicion for APS should be raised in the following settings: Occurrence of one or more otherwise unexplained thrombotic or thromboembolic events One or more specific adverse outcomes related to pregnancy Otherwise unexplained thrombocytopenia or prolongation of a test of blood coagulation ( eg . aPTT )

5. HISTORICAL BACKGROUND Aka “ Hughes syndrome ”. Graham R.V. Hughes linked major cerebral disease (e.g. recurrent strokes) with abortions and the LA in an editorial published in the British Medical Journal in late 1970s and early 1980s. In the Third International Antiphospholipid Conference in 1994 in Leuven, Belgium, his colleagues honored him by naming the syndrome, Hughes syndrome .

6. APS is not synonymous with APLA APLA may also be detected in Healthy individuals Advancing age Lymphoproliferative disease Infection : Syphilis ,HIV , Lyme disease , IMN ,TB Drugs : AED(phenytoin , valproate ) , Procainamide , Chlorpromazine , Hydralazine

7. Recently, the APS ACTION group ( AntiPhospholipid Syndrome Alliance For Clinical Trials and International Networking) published a literature review focused in the prevalence of aPL in the general population. APLA are positive in approx. 13% of all Stroke, 11% of all MI, 9.5% of DVT and 6% of pregnancy morbidity 9% of pregnancy loss Gezer S. Antiphospholipid syndrome. Dis Mon 2003;49(12):696–741 .

8. EPIDEMIOLOGY Prevalence of the APLA in the general population ranges between 1 and 5%. However, only a minority of these individuals develop the APS. The prevalence of the catastrophic APS is scarce ( less than 1% of all cases of APS) Prevalence increases with age ,in elderly with chronic disease F: M = 5:1 Age : Young and middle age adults, mean age- 31 yrs. APLA in 30-40% of SLE pts.

9. PATHOGENESIS Phospholipids are an integral part of platelet and endothelial cell surface membranes. APLA are directed against phospholipid binding proteins. B2GPI is the primary antigenic target of APLA. Under physiologic conditions B2GPI act as elimination of apoptotic cells and as natural anticoagulant 2 hit hypothesis- 1st hit : aPL antibody  thrombophilic state 2nd hit : thrombophilic state  cloting episodes.

10. B2GPI structure

11. PATHOGENESIS

12. PATHOGENESIS cont..

13. Revised Sapporo Classification Criteria for APS Clinical Criteria Vascular thrombosis One or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue or organ Pregnancy morbidity One or more unexplained deaths of a morphologically normal fetus at or beyond 10 th week of gestation One or more premature births of a morphologically normal neonate before 34th wk of gestation because of recognized features of placental insufficiency or 3 or more unexplained consecutive spontaneous abortions before 10th wk of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

14. Sydney Criteria Cont.. Laboratory Criteria Lupus Anticoagulant present in plasma Anti Cardiolipin antibody of IgG or IgM isotype in serum or plasma, present in medium or high titer (> 40GPL or MPL or more than 99th percentile )by ELISA Anti ß2 glycoprotein I antibody of IgG or IgM isotype in serum or plasma(in titre > 99th percentile ) by ELISA (detection of 1 of the above antibodies on 2 or more occasions at least 12 wks apart)

15. LUPUS ANTICOAGULANT

16. ISTH criteria for diagnosis of LA

17. ACLA causes more arterial thrombosis LA causes more venous thrombosis

18. APLA PROFILE High risk Defined as a positive LA test with or without a moderate to-high-titer of aCL or anti-β2GPI IgG or IgM. Moderate risk Defined as a negative LA test with a moderate-to high titer of aCL or anti-β2GPI IgG or IgM. Low risk Defined as a negative LA test with a low titer of aCL or anti-β2GPI IgG or IgM.

19. CLINICAL FEATURES CNS Obstetric Renal (25% 0f pts) Young stroke Cortical sinus thrombosis Multi-infarct dementia, Migraine headache, GBS, Transverse Myelitis Idiopathic Intracranial HTN Chorea Cognitive decline Optic neuritis. Recurrent fetal losses usually after 10th week of gestation, Early eclampsia, HELLP syndrome, IUGR, IUFD, Thrombocytopenia. Proteinuria, ( esp in primary APS) Hematuria, Acute thrombotic micro- angiopathy Glomerulonephritis(25%) RAS and/or severe HTN , Renal vein thrombosis, Renal failure or ESRD

20. Cont.. Cardiac Pulmonary Skin Valvular thickening, Valvular regurgitation, Valvular stenosis, Myocardial infarction, Intracardiac emboli. Pulmonary embolism, Chronic pulmonary thromboembolism, ARDS, Diffuse alveolar hemorrhage Pulmonary hypertension. Livedo reticularis , Ulcerations, Digital gangrene, Subungual splinter hemorrhages, Superficial thrombophlebitis and DVT

21. Cont.. Endocrine manifestation Adrenal insufficiency Autoimmune thyroid disease Hypopituitarism( Sheehan’s syndrome) Hematological Immune hemolytic anemia Thrombocytopenia : usually mild ( < 1 lakh ) If severe ( < 20,000)  CAPS /TTP-HUS

22. MICROVASCULOPATHY Gangrene of toes Livedo reticularis Digital infarct

23. VENOUS THROMBOSIS DVT in the lower extremities : 29% to 55% of pts More than 50% with symptomatic DVT have asymptomatic Pulmonary embolism. Unusual sites of venous thrombosis includes The upper extremities Intracranial veins – acute cerebral infarction Inferior and superior vena cava Hepatic veins (Budd-Chiari syndrome), Portal vein Renal vein and retinal vein.

24. RETINAL VEIN THROMBOSIS

25. ARTERIAL THROMBOSIS Less common than venous thromboses Most commonly present with TIA or stroke (50%) or MI(23%) Presence of ACLA : risk factor for stroke Involvement of large and small vessels—unique feature. NEJM 2002;346;752-63 Dis Mon 2003;49:696-74 Semin Thromb Hemost 1999:25;333-50

26. VALVULAR HEART DISEASE(VHD)IN APS Between 15% - 30% of patients with APS have VHD, k/a Libman -Sacks endocarditis or nonbacterial thrombotic endocarditis( NBTE ) Criteria include Valve thickness >3 mm , Localized thickening of the proximal or middle portion of the valve leaflet, Irregular nodules on the atrial aspect of the mitral valve or the vascular surface of the aortic valve , and/or Moderate-to-severe valvular regurgitation or stenosis

27. Primary APS Genetic predisposition HLA associations: certain HLA genes a/w APS DRw53, DR7 : mostly people of Hispanic origin DR4 : mostly whites Familial association : Relatives of persons with known APS are more likely to have APLA

28. Secondary APS Systemic autoimmune diseases : SLE(most common cause of secondary APS), RA, Systemic sclerosis, Primary Sjogren’s syndrome, Dermato - and polymyositis , Vasculitis (PAN, microscopic polyarteritis , giant cell arteritis, Behçet’s disease, relapsing polychondritis , leucocytoclastic vasculitis). Infections: Viral (HIV ,IMN, rubella, parvovirus, hepatitis A,B, C, mumps), Bacterial (syphilis, Lyme disease, tuberculosis, leprosy, infective endocarditis, rheumatic fever, Klebsiella ), Protozoal (malaria, toxoplasmosis). Drugs : Procainamide, phenothiazines , ethosuximide , chlorothiazide , quinine,OCP , anti- TNFa therapies

29. Cont.. Malignancies: Solid tumors (lung, colon, cervix, prostate, liver, kidney, thymus, esophagus, maxilla, ovary, breast), Hematologic (myeloid and lymphatic leukemias , PV , myelofibrosis ), Lymphoproliferative diseases (HL, NHL, lymphosarcoma , cutaneous T cell lymphoma/ Sezary syndrome), Paraproteinemias (MGUS,WM,MM). Non-malignant hematologic conditions: ITP Sickle cell disease, Pernicious anemia. Other conditions : DM, autoimmune thyroid disease, IBD, Ehlers danlos syndrome.

30. Additional risk factors for thrombosis Age >55 in men and >65 in women Risk factors for CVD Inherited thrombophilias Oral contraceptives Nephrotic syndrome Malignancy Immobilization Surgery

31. CATASTROPHIC APS Preliminary criteria for the classification of catastrophic APS . Evidence of involvement of three or more organs , systems and/or tissues. 2. Development of manifestations simultaneously or in less than a week. 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue. 4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies).

32. CAPS cont.. Definite catastrophic APS: All 4 criteria. Probable catastrophic APS: All 4 criteria, except for only two organs, systems and/or tissues involvement. All 4 criteria, except for the absence of laboratory confirmation at least 6 weeks apart due to the early death of a patient never tested for aPL before the catastrophic APS. 1, 2 and 4. 1, 3 and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension (>180/100 mmHg) and/or proteinuria (>500 mg/24 h).

33. D/D of CAPS Factor V Leiden mutation Homocysteinemia Vasculitis e.g. Classical PAN Infective Endocarditis with embolic phenomena TTP Cholesterol embolism Malignancy HUS Sepsis DIC

34. Approach to a patient with asymptomatic positive APLA

35. Primary Thromboprophylaxis in APS Primary Thromboprophylaxis in Antiphospholipid Syndrome General measures for all antiphospholipid positive pts Assessment and management of traditional cardiovascular risk factors In high-risk situations (puerperium, surgery, prolonged immobilization), use usual doses of LMWH for thromboprophylaxis Antiphospholipid-positive non-SLE patients (obstetric APS and asymptomatic carriers) Low-dose aspirin (75–100 mg/day) in those with a high-risk APLA profile , esp. in the presence of other thrombotic risk factors Patients with SLE and positive APLA Hydroxychloroquine (200–400 mg/day) + low-dose aspirin (75–100 mg/day)

36. Secondary Thromboprophylaxis in APS Secondary Thromboprophylaxis in Antiphospholipid Syndrome Definite APS and a first venous event Indefinite oral anticoagulant therapy to a target INR of 2.0–3.0 Definite APS and arterial thrombosis Indefinite oral anticoagulant therapy to a target INR >3.0 or combined antiaggregant -anticoagulant (INR 2.0–3.0) therapy Patients with venous or arterial thrombosis who do not fulfill c riteria for APS Treatment as per usual recommendations for arterial or venous thrombosis

37. Alternative and Adjunctive Therapeutic Options for Specific Clinical Scenarios in APS Alternative and Adjunctive Therapeutic Options for Specific Clinical Scenarios in Antiphospholipid Syndrome Known warfarin allergy, warfarin intolerance, or poor anticoagulant control on warfarin despite therapeutic target Treatment with, or addition of, NOAC: direct thrombin inhibitor dabigatran or direct anti–factor Xa inhibitors rivaroxaban , apixaban , or edoxaban Heparin-induced thrombocytopenia Treatment with fondaparinux or argatroban Refractory APS despite adequate anticoagulation Consider starting statin therapy Consider adding rituximab therapy Consider adding glucocorticosteroids and IVIG /plasma exchange

38. Cont.. Alternative and Adjunctive Therapeutic Options for Specific Clinical Scenarios in Antiphospholipid Syndrome CAPS Heparin anticoagulation + glucocorticoids + IVIG and/or plasma exchange reduces mortality Eculizumab reduces mortality Renal transplant pts with CAPS Sirolimus decreases recurrent vascular lesions and vascular proliferation Eculizumab for treatment and prevention of thrombotic microangiopathy in patients with history of CAPS

39. Management of Obstetric APS Obstetric APS Heparin (unfractionated or LMWH) + low dose aspirin (75–100 mg/day) Patients on warfarin should be switched to heparin (unfractionated or LMWH) immediately upon pregnancy confirmation to avoid t eratogenicity Extended thromboprophylaxis (up to 6 weeks after delivery) for high-risk patients Indefinite anticoagulation for APS patients with prior thrombotic events

40. Summary of the drug usage in APS Low-dose aspirin (<100 mg per day) Primary thrombosis prevention for CVD prevention in the general population; Secondary arterial thrombosis prevention, if patient has other risk factors for CVD ; Prevention of pregnancy complications in pregnant patients with obstetrical or thrombotic APS or both; Potential add-on treatment for recurrent thrombosis despite therapeutic-dose anticoagulant therapy

41. Summary cont.. Hydroxychloroquine (200–400 mg per day) Potential add-on treatment for recurrent thrombosis despite therapeutic-dose anticoagulant therapy. Statins Potential add-on treatment for recurrent thrombosis despite therapeutic-dose anticoagulant therapy. Warfarin Secondary thrombosis prevention (INR, 2–3); Target INR of 3–4 is a possible strategy for recurrent thrombosis despite therapeutic dose anticoagulant therapy

42. Summary cont.. Low-molecular-weight heparin Thrombosis prevention during high-risk periods (e.g., perioperative or postpartum period); Prevention of thrombosis and pregnancy complications in pregnant patients with obstetrical APS (e.g., enoxaparin, 40 mg daily) and thrombotic APS (e.g., enoxaparin, 1.5 mg/kg of body weight daily or 1 mg/kg twice daily); Potential alternative treatment for recurrent thrombosis despite therapeutic dose warfarin (e.g., enoxaparin, 1.5 mg/kg daily or 1 mg/kg twice daily)

43. Summary cont.. Unfractionated heparin Part of first-line combination treatment for catastrophic APS; Prevention of thrombosis and pregnancy complications in pregnant patients with obstetrical APS (5000 units subcutaneously twice daily) and thrombotic APS (e.g., 250 units/kg subcutaneously twice daily) Direct oral anticoagulants More data needed

44. Summary cont.. Glucocorticoids (e.g., IV methylprednisolone,250–1000 mg for 3 days) Part of first-line combination treatment for catastrophic APS; First-line treatment for severe thrombocytopenia, hemolytic anemia, or both. Intravenous immune globulin Part of first- or second-line combination treatment for catastrophic APS (1–2 g/kg, given over a period of 3–5 days); First- or second line treatment for severe thrombocytopenia (1 g/kg; can repeat once, usually 1–2 days after first dose)

45. Summary cont.. Plasma exchange Part of first- or second-line combination treatment for catastrophic APS; for acute thrombotic micro- angiopathy in patients with aPL related nephropathy Traditional immunomodulatory agents (e.g., azathioprine, 100–150 mg per day, or MMF, 1000–3000 mg per day) An option for severe thrombocytopenia, hemolytic anemia, or both; An option for aPL nephropathy

46. Summary cont.. Rituximab (e.g., 1000 mg on days 0 and 15, repeated every 6 mo ) An option for thrombocytopenia, hemolytic anemia, livedoid vasculopathy , and aPL nephropathy; An option for catastrophic APS that is refractory to standard treatment Eculizumab An option for catastrophic APS that is refractory to standard treatment; An option for acute thrombotic microangiopathy in patients with aPL -related nephropathy Defibrotide More data needed

47. TAKE HOME MESSAGE

48. Reference Wintrobes clinical hematology 13 th edition Harrison 19 th edition N Engl J Med 2018; Diagnosis and Management of the Antiphospholipid Syndrome ASH hematology APS 2015 Journal of ACG 2017 APS

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50. NETosis Upon activation, neutrophils release fibers composed of chromatin and neutrophil proteins termed neutrophil extracellular traps (NETs). NETs trap and kill microbes, activate dendritic cells and T-cells , and are implicated in auto-immune and vascular diseases.

51. DEFIBROTIDE Adenosine receptor agonist Approved for hepatic veno -occlusive disease (also known as the sinusoidal obstruction syndrome) after hematopoietic stem-cell transplantation. Adenosine 2A receptor agonism  triggers cAMP formation in neutrophils Lower thrombotic risk by reducing antiphospholipid antibody–mediated NETosis