MODERATOR: Dr Manika Agarwal Associate Prof, Dept of Obs & Gyn, NEIGRIHMS Presented by : Sattradhaja Keisham 2008- Batch intern, Dept. of Obs & Gyn, NEIGRIHMS OUTLINE Discovery of APS A brief review of APS Introduction Clinical features Pathophysiology Etiology Epidemiology Diagnostic criteria Prognosis Approach of APS in Pregnancy History and physical findings Approach considerations
Management of APS Obstetrics care Medical Management Management in the future Summary
DISCOVERY OF APS (HUGHES SYNDROME) Professor Graham Hughes Consultant Rheumatologist, Head of The London Lupus Centre
Professor Graham Hughes trained and qualified at The London Hospital. In 1969 - 1970 he spent two years Postgraduate Fellowship in New York at the Rheumatology & Lupus Centre of Dr Charles Christian. Professor Hughes became a Consultant Physician at Hammersmith Hospital where he set up Europes first dedicated Lupus Clinic in 1973. In 1983 he described the clotting disorder now known as Hughes Syndrome. In 1985 he set up the Lupus Unit at St Thomas Hospital. In 1993 he received the World Rheumatology (ILAR) Research Prize for the description of Hughes Syndrome. He is a member of the American Lupus Hall of Fame, and Doctor Honoris Causa at the Universities of Marseille and Barcelona. Prof. Graham Hughes ANTIPHOSPHOLIPID SYNDROME
A BRIEF REVIEW INTRODUCTION Antiphospholipid Syndrome (APS) is an autoimmune thrombophilic condition that is marked by the presence in blood of antibodies that recognize and attack phospholipid-binding proteins, rather than phospholipid itself. APS is associated with pregnancy complications : - preeclampsia, - thrombosis, - autoimmune thrombocytopenia, - fetal growth restriction, and - fetal loss.
APS is classified as Primary or Secondary, depending on its association with other autoimmune disorders. Primary APS is diagnosed in patients demonstrating the clinical and laboratory criteria for the disease without other recognized autoimmune disease. Secondary APS is diagnosed in patients with other autoimmune disorders, such as SLE.
It represents the severe end of the spectrum with multiple organ thromboses in a rapid period of time. It has a mortality rate of approximately 50%. Multiorgan failure has been seen during pregnancy and also during postpartum. The clinical spectrum of this syndrome has widened, with important advances in the knowledge of its pathogenesis and clinical management made during the past several years.
INTRODUCTION Types of patients having antiphospholipid (aPL) antibodies
I. Antiphospholipid syndrome A. Primary in the absence of SLE B. Secondary in patients with SLE II. aPL antibodies stimulated by infection A. No known association with thrombosis (e.g., syphilis, Lyme disease, cytomegalovirus, Epstein-Barr virus) B. Possible association with thrombosis (e.g., varicella, HIV, hepatitis C) III. Drug-induced aPL antibodies (e.g. chlorpromazine and other phenothiazides) IV. aPL antibodies prevalent in the general population (asymptomatic or seronegative APS) Do all people with high aPL antibodies have APS? CLINICAL FEATURES OF APS Nonobstetric features of APS are as follows: 1) Peripheral venous system - deep venous thrombosis [DVT]) 2) Central nervous system - cerebrovascular accident [CVA], sinus thrombosis 3) Hematologic - thrombocytopenia, hemolytic anemia 4) Pulmonary - pulmonary embolism [PE], pulmonary hypertension 5) Dermatologic - livedo reticularis, purpura, infarcts/ulceration 6) Cardiac - Libman-Sacks valvulopathy, MI 7) Ocular - amaurosis, retinal thrombosis 8) Adrenal - infarction/hemorrhage 9) Musculoskeletal - avascular necrosis of bone CLINICAL FEATURES OF APS Obstetric features of APS are as follows:
1) Fetal death or stillbirth 2) Recurrent pregnancy loss - 3 or more spontaneous abortions 3) Second or Third trimester fetal death 4) Severe preeclampsia - at less than 34 weeks gestation 5) Unexplained severe fetal growth restriction 6) Chorea gravidarum
PATHOPHYSIOLOGY Biologic effects mediated by the human aPL antibodies include the following:
1) Reactivity with endothelial structures that disturbs the balance of prostaglandin E2/thromboxane production 2) Interaction with platelet PLs, with consequent upregulation of platelet aggregation 3) Dysregulation of complement activation 4) Interaction of aPL with phosphatidylserine exposed during trophoblast syncytium formation, which raises the possibility of a more direct effect of these autoantibodies on placental structures
ETIOLOGY Like other autoimmune disorders, ASP does not have a known etiology. There are several hypotheses to explain the probable cause :
Passive transfer of maternal antibodies mediate autoimmune disorders in the fetus and newborn. The mechanism of excess autoantibody production and immune complex formation is not well understood.
Familial occurrence of aPL has been reported, and suggested genetic associations include HLA-DR4, DR7, DRw53 and C4 null allele.
PL molecules are ubiquitous in nature and are present in the inner surface of the cell and in microorganisms. Therefore, during infectious disease processes, including viral (eg, HIV, EBV, CMV, adenoviruses), bacterial (eg, bacterial endocarditis, tuberculosis, Mycoplasma pneumonia), spirochetal (eg, syphilis, leptospirosis, Lyme disease), and parasitic (eg, malaria infection),the disruption of cellular membranes may occur during cell damage. EPIDEMIOLOGY APS accounts for about 19% to 20% of RPL in the world. The prevalence of aCL and LAC in normal healthy populations has been reported to range between - 1.0% and 5.6% for aCL, and - 1.0% and 3.6% for LAC. Age group : 20 yrs to 50 yrs. The prevalence of elevated aPL antibodies, particularly aCL tend to increase with age . Sex : Female predominance of about 80% of APS patients (owing to secondary APS in SLE). Race : no defined racial predominance for primary APS, although SLE is more common in African Americans and Hispanic populations. Geographical distribution : still at infancy stage of data collection. Hereditary predilection : some reports available, however, it is still difficult to determine genetic risk factors for aPL and APS because of the heterogeneity in the antigen specificity, and pathogenesis of the clinical manifestations of APS. EPIDEMIOLOGY. Risk factors for APS: In SLE patients, 33% are aCL posivitive and LA prevalence is about 15% . A positive LA appears to be more specific for APS than an elevated aCL. The strength of the association between aPL and thrombosis varies. Primarily, aCL are not as strong a risk factor for thrombosis as LA. Lupus anticoagulant is conistently the most powerful predictor of thrombosis . About 40% of patients with SLE have aPL, but less than 40% of them will eventually have thrombotic events . Titer and isotype are important: IgG aCL is more strongly associated with clinical events than is IgM aCL, and the risk of thrombosis increases with higher titers (>40 U). IgA aCL and low titers of IgG and IgM aCL are less frequently associated with complications . Second-hit hypothesis - a second trigger event - such as cigarette smoking, oral contraceptives etc. surgical procedures, prolonged immobilization, or a genetic prothrombotic state - may increase the likelihood of an aPL positive patient developing a vascular event. Women with pregnancy events alone have a high likelihood of developing thrombosis in later years .
DIAGNOSTIC CRITERIA FOR APS The diagnosis requires that the patient have at least 1 clinical and 1 laboratory criterion.
(updated 2009) Clinical criteria 1.Vascular thromboses 1 or more documented episodes of arterial, venous, or small vessel thrombosis - other than superficial venous thrombosis- in any tissue or organ. Thrombosis must be confirmed by objective validated criteria. For histopathologic confirmation,thrombosis should be present without significant evidence of inflammation in the vessel wall.
2. Pregnancy morbidity (a) 1 or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or (b) 1 or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or severe pre-eclampsia defined according to standard definitions, or (ii) recognized features of placental insufficiency, or (c) 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded. DIAGNOSTIC CRITERIA FOR APS.. Laboratory criteria
Anticardiolipin antibodies - Anticardiolipin IgG or IgM antibodies present at moderate or high levels (ie, >40 GPL or MPL or >99th percentile) in the blood on 2 or more occasions at least 12 weeks apart
Lupus anticoagulant - LAC detected in the blood on 2 or more occasions at least 12 weeks apart
Anti-beta 2 -glycoprotein I antibodies IgG or IgM - In titers above the 99th percentile for normal as defined by the laboratory performing the test, on 2 or more occasions at least 12 weeks apart
DIAGNOSTIC CRITERIA FOR APS .. Additional findings in APS:
The following findings may also provide strong clues to the diagnosis of APS, irrespective of the clinical and laboratory criteria:
1) Unexplained transient ischemic attacks or amaurosis fugax 2) Positive result from the Coombs test 3) Hemolytic anemia 4) Chorea 5) Chorea gravidarum OTHER HELPFUL INVESTIGATIONS FOR APS
Immunoassays I. Biologic false-positive serologic test for syphilis II. Anticardiolipin antibodies (cofactor-dependent assay) III. Antiphosphatidylserine antibodies IV. Antiprothrombin antibodies
Coagulation Tests I. Dilute Russell viper venom time (DRVVT) with confirmatory tests II. aPTT :
III. Kaolin clotting time IV. Plasma clotting timeCY evidence of inhibitor with mixing studies panel of aPL-sensitive and insensitive aPTT reagents platelet neutralization procedure PROGNOSIS Maternal morbidity Thrombosis, which may may also be associated with anticoagulation in patients treated with heparin or lowmolecular-weight heparins in pregnancy. women with APS have an increased incidence of preeclampsia, which, when it occurs, frequently develops prior to 34 weeks gestation. The incidence of severe preeclampsia requiring premature delivery is also increased. APS is also associated with infertility and pregnancy complications, such as spontaneous abortions, prematurity, and stillbirths. Landry-Guillain-Barr-Strohl syndrome (LGBSS) although exceedingly rare in pregnancy, can occur in patients with APS and lupus. i. Patients usually present with progressive bilateral and symmetrical muscle weakness accompanied by mild sensory symptoms, including paresthesia, numbness, and tingling. The disease can progress to involve the respiratory muscles, resulting in respiratory failure. Two thirds of the patients have a history of viral-like infections 1-3 weeks prior to the onset of symptoms. ii. CMV infection has been incriminated as a potential etiologic agent in some pregnant patients presenting with LGBSS.
Maternal mortality Mortality rates during pregnancy are not well characterized. Multiorgan failure has been described during pregnancy by Asherson [2] and during postpartum by Kochenour. [3]
PROGNOSIS. Perinatal morbidity The aPL antibodies are found in 10-15% of women at high risk for fetal growth restriction. Neonatal morbidity and mortality may be influenced by indicated preterm delivery for maternal severe preeclampsia or fetal growth restriction. Neonatal lupus dermatitis, a variety of systemic and hematologic abnormalities, and isolated congenital heart block have been associated with APS and SLE. Perinatal mortality Fetal deaths at or beyond 20 weeks' gestation may be attributable to APS involvement. The rate of fetal loss may exceed 90% in untreated patients with APS. Therapy (including aspirin and heparin) can reduce the rate of fetal loss to 25%, as described by Cowchock et al.
APPROACH OF APS IN PREGNANCY HISTORY AND PHYSICAL FINDINGS (APS) The diagnosis of APS is based primarily on clinical history and laboratory data. Thrombosis and stroke are possible residual neurologic findings in APS. Tinnitus, ear ache, dizzy spells, headaches, migraines, memory lapses, etc are usual neglected symptoms which may actually indicate poor circulation and transient ischaemic attacks. Aortic Angina Cutaneous manifestations of APS can include the following: 1. Digital cyanosis 2. Livedo reticularis 3. Digital gangrene 4. Leg ulcers 5. Discoid rash 6. Photosensitivity
Pic 1. Digital cyanosis Pic 2. Livedo reticularis Pic 3. Digital gangrene Pic 4. Discoid rashes APPROACH CONSIDERATIONS Pregnant women with APS are considered high-risk obstetric patients, and medical care is instituted with this in mind.
1. In patients receiving or recently treated with corticosteroid therapy , administer supplementation to cover the labor or cesarean delivery. Therapeutic abortions are generally not indicated in pregnant women with autoimmune disease. 2. Epidural anesthetic is not recommended if the mother has a marked drop in the maternal platelet count. The use of forceps or the vacuum extractor should be individualized. 3. No evidence indicates adverse effects related to breastfeeding, although breastfeeding is not recommended if high doses of cytotoxic or immunosuppressive agents are required.
MANAGEMENT OF APS OBSTETRIC CARE 1. Preconception counselling : Patients should be counseled in all cases regarding symptoms of thrombosis and thromboembolism and should be educated regarding, and examined frequently for, the signs or symptoms of thrombosis or thromboembolism, severe preeclampsia, or decreased fetal movement. 2. Ultrasonography : is recommended every 3-4 weeks starting at 18-20 weeks gestation, in patients with a poor obstetric history, evidence of preeclampsia, or evidence of fetal growth restriction. 3. In patients with uncomplicated APS, ultrasonography is recommended at 30-32 weeks gestation to assess fetal growth. Lagging fetal growth may reflect uteroplacental insufficiency in patients with APS. 4. hCG values in the first trimester can be followed to evaluate the viability of the pregnancy. If hCG levels are increasing normally (ie, doubling every 2 days) in the first month of pregnancy, a successful outcome is predicted in 80-90% of cases. However, when the increases are abnormal (ie, slower), a poor outcome is predicted in 70- 80% of cases. 5. Stop cytotoxic Drugs several months prior to becoming pregnant. MEDICAL CARE OF APS IN OBSTETRIC PATIENT Seronegative APS i.e. without previous thrombosis and recurrent early (pre-embryonic or embryonic) miscarriage
Lowdose Aspirin alone or together with either unfractionated heparin (50007500 IU SC every 12 h) Or LMWH (usual prophylactic doses: Enoxaparin 40 mg SC every 24 h). If aspirin was used before pregnancy, it must be switched to low dose heparine at the time of pregnancy.
Following delivery, postpartum thromboprophylaxis with warfarin or LMWH is indicated. MEDICAL CARE APS without previous thrombosis and fetal death more than 10 weeks gestation or previous early delivery (<34 weeks gestation) due to severe pre-eclampsia or placental insufficiency
Low-dose aspirin plus unfractionated heparin (750010 000 IU subcutaneoulsy every 12 h in the first trimester; 10 000 U subcutaneously every 12 h in the second and third trimesters, or every 812 h adjusted to maintain the mid-interval aPTT* 15 times the control mean) or LMWH (usual prophylactic doses: Enoxaparin 40 mg SC every 24 h). Following delivery, postpartum thromboprophylaxis with warfarin or LMWH is indicated.
MEDICAL CARE APS with thrombosis
Low-dose aspirin plus unfractionated heparin (subcutaneously every 8 12 h adjusted to maintain the midinterval aPTT* or heparin concentration (anti-Xa activity)* in the therapeutic range) or LMWH (usual therapeutic dose-eg, enoxaparin 1 mg/kg subcutaneously, or dalteparin 100 U/kg subcutaneously every 12 h, or enoxaparin 15 mg/kg/day subcutanously, or dalteparin 200 U/kg/day subcutaneously)
MEDICAL CARE APS with prior fetal death or recurrent pregnancy loss
If Pregnant a. Heparin in prophylactic doses (15000-20000 U of unfractioned heparin or equivalent per day) administerd SC in divided doses with low dose aspirin daily. b. Calcium and vitamin D supplementation
If non-pregnant a. Optimal management is uncertain; options include no treatment or daily treatment with low-dose aspirin MEDICAL CARE APS with prior thrombosis or stroke
If Pregnant : Heparin to achieve full anticoagulation(does not cross placenta)
Non pregnant : Warfarinadministered daily in doses to maintain INR of = 3 MEDICAL CARE Pregnant LGBSS : High dose iv IG at 400-1500 mg/kg/day for several days
Non pregnant LGBSS : iv IG at 400-1500 mg/kg/day for several days PERSONAL CARE OF APS PATIENT Consultations : Rheumatologist Hematologist Neurologist, cardiologist, pulmonologist, hepatologist, ophthalmologist (depending on clinical presentation) Obstetrician with experience in high-risk pregnancies
Diet : If warfarin therapy is instituted, instruct the patient to avoid excessive consumption of foods that contain vitamin K.
Activity : No specific limitations on activity are necessary. Individualize the activity according to the clinical setting. Instruct the patient to avoid sports with excessive contact if taking warfarin. Limit activity in patients with acute DVT. Instruct the patient to avoid prolonged immobilization.
MANAGEMENT OF APS IN THE FUTURE Potential future therapies for antiphospholipid syndrome :
Combination antiaggregant therapy (low-dose aspirin plus clopidogrel or dipyridamole) Oral antifactor Xa drugs (rivaroxaban, apixaban) Direct thrombin inhibitors (dabigatran) B-cell depletion (rituximab) Statins (fluvastatin, rosuvastatin) Hydroxychloroquine SUMMARY OF APS MANAGEMENT 1. In women with well-recognized obstetric APS, anticoagulant prophylaxis is recommended during pregnancy and the postpartum period. 2. Pregnant women with APS are considered at risk for thrombosis and pregnancy loss. 3. Data suggest low-dose aspirin and heparin (either unfractionated heparin or LMWH) to be the treatments of choice for prevention of pregnancy loss in pregnant women with APS and previous pregnancy losses. 4. Pregnant women with APS and a history of thrombosis but no pregnancy loss require only treatment with heparin. 5. Treatment is optional for patients with no history of pregnancy loss or thrombosis
REFERENCES 1. Hughes GR: Thrombosis, abortion, cerebral disease and the lupus anticoagulant. BMJ 1983, 287:1088- 1089. 2. Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-44. 3. Roubey RAS, Hoffman M. From antiphospholipid syndrome to antibody-mediated thrombosis. Lancet 1997; 350:1491-3. 4. Khamashta MA, Cervera R, Asherson RA, Font J, Gil A, Coltart DJ, Vzquez JJ, Par C, Ingelmo M, Oliver J, et al. Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet 1990; 335:1541-1544. 5. Mialdea M, Sangle SR and D'Cruz DP. Antiphospholipid (Hughes) syndrome: beyond pregnancy morbidity and thrombosis. Journal of Autoimmune Diseases 2009;19:6:3. 6. Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJ, Barquinero J, et al. The "primary" antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore). Nov 1989; 68(6):366-74. 7. Kochenour NK, Branch DW, Rote NS, et al. A new postpartum syndrome associated with antiphospholipid antibodies. Obstet Gynecol. Mar 1987; 69(3 Pt 2):460-8. Etc etc etc.
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