The Antiphospholipid Syndrome 三軍總醫院風濕免疫過敏科 陳 政 宏 醫師

Antiphospholipid syndrome

SLE complicated with APS

Major features of the APS Clinical Venous thrombosis Arterial thrombosis Recurrent fetal loss Thrombocytopenia Laboratory IgG ACAs(moderate/high level) IgM ACAs(moderate/high level) Positive lupus anticoagulant test

Incidence and epidemiology(1) oGeneral population:Prevalence7.5% for ACA determinations(In Southern Californian health women), 1.79% in pregnant women(IgG ACA) and 4.3% for IgM ACA, ACA may be associated with an age-related senescent immune system(>12% in elder population) oSLE:APLA 6~80% oOther autoimmune disease:part of natural form of repertoire of Abs, not pathogenic. oInfection: The APLAs may be produced as a consequence of variety of infection(HIV,CMV, EBV, parovirus, hepatitis A,B,C, mumps and rubella, syphilis, Lyme disease, TB, leprosy, infective endocarditis, rheumatic fever, protozoal infection).

Incidence and epidemiology(2) oMalignancy:A variety of malignant conditions may be acompanied by APLA, occasionally, disappearance of APLA after surgical resection of tumor has been reported. oHematologic condition:ITP, sickle cell disease, pernicious anemia oDrug-induced APLAs:Same compounds responsible for the drug-induced lupus-like syndroem(procainamide, phenothiazine, ethosuximide, chlorothiazide, quinine and oral contraceptives) oOther associations: DM,autoimmune thyroid diease, inflammatory bowel disease, dialysis, Klinefelter ’ s syndrome.

Systemic autoimmune disease with APS SLE RA Systemic sclerosis Primary Sj ö gren syndroem Dermatomyositis Plymyositis Psoriatic arthropathy Vasculitis PAN, microscopic polyarteritis Giant cell arteritis Behcet ’ s disease Relapsing polychondritis Leukocytoclastic vasculitis Mesentric inflammatory venoocclusive disease Capillitis Other type of vasculitis

Infections with APLAs Viral: HIV, Mononucleosis, Parovirus, Hepatitis A,B,C, Mumps Bacterial: Syphilis, Lyme disease, TB, Leprosy, Infective endocarditis, Rheumatic fever, Klebsiella species infection Protozoal: Malaria, Toxoplasmosis

Malignancies with APLAs Solid tumors Lung Colon, rectum Cervix Kidney(Hypernephroma) Thymus(thymoma) Esophagus Maxilla Ovary Breast Hematologic Myeloid & lymphatic leukemia Polycythemia vera Myelofibrosis Lymphoproliferative diseases Hodgkin ’ s disease Non-Hodgkin ’ s lymphoma Lymphosarcoma Cutaneous T-cell lymphoma Paraproteinemias Monoclonal gammapathies Myeloma Waldenstrom ’ s macroglobulinemia

Clinical presentation oLarge Vessel manifestations oNeurological manifestations oCardiac manifestations oPulmonary manifestations oRenal manifestations oHepatic manifestations oOsteoarticular manifestations oDermatologic manifestations oHematologic Manifestations oDigestive manifestations oObstetric manifestations

Large vessel manifestations: DVT  The most frequently reported association with APLA is DVT.  DVT is frequently multiple, bilateral, affecting lower limbs.  Superficial thrombophlebitis may accompany DVT.  DVT may accompany chronic venous stasis ulcers.  DVT is also complicated by pulmonary embolism and infarction.  Recurrent thromboembolism may lead to pulmonary hypertension.  Venous occlusion  superior vena cava syndrome, renal vein thrombosis, hypoadrenalism or Addison ’ s disease, Budd-Chiari syndrome, or central retinal vein occlusion

Large vessel manifestation: Large peripheral arterial occlusions  The first paper to describe in detail large peripheral occlusions in SLE was published in  Livedo reticularis, chronic leg ulcers, recurring thrombophlebitis, skin infarctions, and other arterial occlusions  Aortic arch syndrome have been reported in SLE, abdominal aorta occlusion also been documented

Neurologic manifestations Thrombotic infarction Sneddon ’ s syndrome TIA Multiinfarct dementia Acute ischemic encephalopathy Embolic stroke Cerebral venous & dural sinus thrombosis Psycosis Cognitive defect Transient global amnesia Pseudomultiple sclerosis Migraine and migranous stroke Epilepsy Movement disorder(Chorea, cerebellar ataxia, hemiballismus) Spinal syndrome(Transverse myelopathy, GBS) Ophthalmic complications(retinal vessel occlusion, acute retrobulbar optic neuritis, ischemic optic atrophy)

1. The thoracic spine shows diffuse central cord edema extending from the level of T2 to the level of T11, demonstrating high signal abnormalities in the central cord on T2WI. The cord edema is not associated with mass effect or enhancement. Syrinx is not likely. In light of prior history of optic neuritis and thalamic lesions, multiple sclerosis with spinal cord involvement is highly suspected. Moreover, because the patient is a victum of SLE, SLE involvement of the cord is also possible the underlying cause but is much rare. 2. The size, shape and alignment of the thoracic spine are normal.

Cardiac manifestations in Antiphospholipid Syndrome  Myocardial infarction  Unstable angina  Coronary bypass graft and angioplastic occlusions  Cardiomyopaty  Vavular disease(valve thickening & deformity, vegetations, pseudoinfective endocarditis)  Intracardiac thrombus  Cyanotic congenital heart disease  Complication of cardiovascular surgery

Categories of patients in which APS- associated coronary disease should be most suspected  Myocardial infarction or ischemia M or F patient less than 45 years old Patient with diagnosed autoimmune disease Patient of any age without any risk factors for atherosclerosis Normal or near-normal appearing coronary arteries after thrombolytic therapy MI despite concurrent therapy with warfarin or aspirin  Aortocoronary graft closure Occlusion of vein grafts < 1 year after surgery Occlusion despite anticoagulation with warfarin and aspirin  PTCA: Reocclusion of successfully dilated arteries within 3 months of angioplasty Reocclusion despite warfarin or aspirin therapy

Pulmonary manifestations  Pulmonary embolism & infarction  Pulmonary hypertension  Pulmonary arterial occlusions  Adult respiratory distress syndrome  Intraalveolar pulmonary hemorrhage  Fibrosing alveolitis  Postpartum syndrome

Renal Manifestations  Glomerular Capillary thrombosis in lupus nephritis  Intrarenal vascular lesions (thrombotic microangiopathy)  Renal artery occlusion  Renal vein thrombosis  End-stage renal failure and hemodialysis  Post-renal transplantation thrombotic complications  Pregnancy and post-partum syndrome

Adrenal manifestations  Adrenal vein thrombosis  adrenal insufficiency, adrenal hemorrhagic infarction, usually bilateral

Hepatic manifestations  Budd-Chiari syndrome  Portal hypertension  Obstruction of small hepatic veins  Nodular regenerative hyperplasia  Hepatic infarction  Hepatitis:CAH  Alcoholic liver disease  Cirrhosis of liver

Digestive manifestations  Esophagus necrosis  Gastric ulceration  Small and large bowel occlusion  Mesentric inflammatory vasoocclusive disease  Inflammatory bowel disease  Pancreatitis  Cholecystitis  Occlusion of splenic vessels

Obstetric manifestations  Maternal complication: Toxemia, preeclampsia, HELLP syndrome(hemolysis, elevated liver enzyme,low platelet counts and severe pre-eclampsia), postpartum cardiopulmonary syndrome, chorea gravidarum, postpartum cerebral infarction  Fetal complication: abortion, fetal death, intrauterine growth retardation, abruptio placenta, neonatal stroke, disseminated neonatal thrombosis.

Osteoarticular manifestations  Avascular necrosis of bone  Arthralgia and arthritis  Myositis

Dermatologic manifestations  Livedo reticularis  Skin ulceration  Small, painful leg ulcer of livedoid vasculitis  Cutaneous necrosis  Macules and nodules  Multiple subungual hemorrhage  Gangrene and digital necrosis

Hematologic manifestations  Thrombocytopenia  Coomb ’ s test positivity and hemolytic anemia  Neutropenia  Microangiopathic syndrome  Catastrophic APS  Thrombotic microangiopathic hemolytic anemia  Disseminated intravascular coagulopathy  HELLP syndrome(hemolysis, elevated liver enzyme, low platelet) in pre-eclampsia patient.

PATHOGENESIS:POSSIBLE MECHANISMS

Diagnostic testing  Lupus anticoagulant tests: It depend on the ability of some groups of APLA to prolong phospholipid-depentent in vitro clotting system(aPT, Russell viper venom clotting time, kaolin clotting time, PT determined by dilute thromboplastin)  Solid-Phase technique to detect anticardiolipin Antibodies: include ELISA & radioimmuneoassay  Serologic test for syphilis.  Solid-Phase techniques to detect other antiphospholipid antibodies(phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylcholine, etc.)  Solid-Phase technique to detect antibodies to cofactors of APLA: ß 2-GPI(a natural anticoagulant along with protein C,S, antithrombin-III)

Treatment  Asymptomatic disease:Prophylaxis is controversial.  Thrombosis:life-long anticoagulants treatment, warfarin 20mg/day, maintain INR 2~3, use of new antiplatelet agents  Prophylaxis for fetal loss: low-dose aspirin(50-100mg/day) from the beginning of pregnancy until just before delivery, may combine with daily subcutaneous heparin(low molecular heparin)  Thrombocytopenia: low-dose aspirin & warfarin, other immunesuppressive agent, danazol, IVIG.  Catastrophic APS:Adequate anticoagulant therapt, pulse steroid, cyclophosphamide, plasmapheresis.