definition Antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS or) is an autoimmune,hypercoagulable state caused by antibodies against cell-membrane phospholipids that provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, or severe preeclampsia. The syndrome occurs due to the autoimmune production of antibodies against phospholipid (aPL) of the cell membranes. In particular, the disease is characterised by antibodies against cardiolipin(anti-cardiolipin antibodies) and β2 glycoprotein I
Clinical types . The term "primary antiphospholipid syndrome" is used when APS occurs in the absence of any other related disease. APS however also occurs in the context of other autoimmune diseases, such as systemic lupus erythematosus (SLE), in which case the term "secondary antiphospholipid syndrome" is used. In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed "catastrophic antiphospholipid syndrome" (CAPS) and is associated with a high risk of death.
presentations APS presents in two major ways: 1-thrombosis (venous or arterial) 2-pregnancy loss. Thrombocytopenia, present in about 20% of cases, canbe an important clue.
EPIDEMIOLOGY Race No defined racial predominance for primary APS has been documented, although SLE is more common in African American and Hispanic populations. Sex A female predominance has been documented, particularly for secondary APS. This parallels the association of APS with SLE and other connective- tissue diseases, Age APS is more common in young to middle-aged adults; however, it also manifests in children and elderly people. .
EPIDEMIOLOGY In patients presenting with a deep venous thrombosis, up to 30% will have the APS. In a person under age 50 with a stroke, up to 46% will have APS. About 8% of primary APS patients later develop SLE In SLE patients, about 30% have anticardiolipin and about 25% have the lupus anticoagulant. The risk of venous thrombosis in a SLE patient with the lupus anticoagulant is 50% by 20 years after diagnosis.
PATHOGENESIS The pathogenesis of APS is complex and multifactorial, reflecting the fact that aPL bind to plasma proteins and to endothelial cells involved in multiple steps in coagulation. APL interfere with the activated protein C complex and also bind to platelets. They bind to endothelial cells, leading to upregulation of cytokines and tissue factor.
Clinical features Antiphospholipid syndrome (APS) is a heterogenous disorder in terms of clinical manifestations and range of autoantibodies. major clinical features may present: 1-Vascular thrombosis One or more clinical episodes of arterial, venous, or small-vessel thrombosis . Thrombosis may involve the cerebral vascular system, coronary arteries, pulmonary system (emboli or thromboses), arterial or venous system in the extremities, hepatic veins, renal veins, ocular arteries or veins, or adrenal glands. 2-Pregnancy morbidity One or more late-term (>10 weeks gestation) spontaneous abortions Three or more unexplained, consecutive, spontaneous abortions before 10 weeks’ gestation
Clinical featuresHistory of any of the following should raise theexaminers suspicion for APS:1-Thrombosis (eg, DVT/PE, MI, transient ischemic attack [TIA], or CVA,especially if recurrent, at an earlier age, or in the absence of other knownrisk factors).2-Miscarriage (especially late trimester or recurrent) or premature birth3-History of heart murmur or cardiac valvular vegetations4-History of hematologic abnormalities, such as thrombocytopenia orhemolytic anemia5-History of nephropathy6-Nonthrombotic neurologic symptoms, such as migraine headaches,chorea, seizures, transverse myelitis, Guillain-Barré syndrome, or dementia(rare)7-Unexplained adrenal insufficiency8-Avascular necrosis of bone in the absence of other risk factors9-Pulmonary hypertension
CLINICAL FEATURES livedo reticularis, a purplish lacelike reticular pattern,especially apparent on the extremities.
Clinical features Catastrophic APS : is a rare presentation with multiorgan thrombi . Precipitants of catastrophic APS include infection, surgery, pregnancy,exogenous estrogen, and cessation of anticoagulation.N.B: In the evaluation of APS, it is necessary to exclude genetic and acquired causes of hypercoagulability Thrombosis can occur even in the presence of thrombocytopenia
LABORATORY FEATURES1-Lupus Anticoagulant only 50% of patients with LA have lupus. To confirm the presence of an LA, these criteria are required:
Lab features: lA2. A sensitive activated partial thromboplastin time (aPTT) is recommended for screening.Prolongation of the clotting time must be due to an inhibitor (rather than a factor deficiency). This is confirmed by demonstrating that the prolonged clotting time does not correct with a 1 : 1 or 4 : 1 mix with normal plasma.
Lab features3-Anticardiolipin Anticardiolipin (aCL) is actually an antibody directed against negatively charged phospholipids bound to beta 2 glycoprotein I. Only medium-to-high titers of the IgG or IgM isotype are accepted for the classification criteria.4-Anti–Beta 2 Glycoprotein IThus, anti-beta 2 GPI is rarely necessary to make the diagnosis/classifi cation of APS.
Diagnostic CRITERIA FOR ANTIPHOSPHOLIPID SYNDROME (sydney revision) One clinical criterion 1-Thrombosis Arterial Or Venous or Vasculopathy 2-pregnancy morbidity a- 3 or more first trimester losses b- or 1 or more late fetal losses c- Or Severely preterm birth due to placental insufficiency PLUS One laboratory criterion: persistent over 3 months Lupus anticoagulant (present twice over 3 month) OR Moderate/high titer IgG or IgM anticardiolipin OR Moderate/high titer IgG or IgM anti–beta 2 glycoprotein I SOURCE: From Miyakis S, et al. J Thromb Haemost 2006;4:295–306, by permission of Journal of Thrombosis and Haemostasis.
complications Antiphospholipid syndrome (APS) complications happen to only a minority of patients with aPL. Several features are thought to increase the risk of thrombosis:1-including the lupus anticoagulant (over aCL)2- high titers of Acl3- persistence of aPLs for longer than 6 months,4-comorbid factors including estrogen, thalidomide, nephrotic syndrome, bed rest, surgery, pregnancy, and the postpartum period
treatment Asymptomatic Antiphospholipid Antibodies Patients with aPL but no history of thrombosis or pregnancy loss 1- should avoid medications that might contribute to hypercoagulability, including oral contraceptives and hormone therapy 2-. Other risk factors for hypercoagulability should be minimized.3- Low dose aspirin can be considered as a prophylactic therapy, but efficacy has not been proven in clinical trials.4- hydroxychloroquine can be considered as a possible prophylactic intervention in SLE patients.
treatment Pregnancy Loss For it ‘s prevention prophylactic doses of unfractionated or low- molecularweight heparin plus low dose aspirin (81 mg)This regimen causes less maternal and pregnancy morbidity than the older regimens of prednisone and aspirin.Unfortunately, the heparin and aspirin regimen is successful in only 75% of pregnancies.If unsuccessful, there is some scientific rationale tothe addition of intravenous immunoglobulin in the nextpregnancy.
TreatmentThrombosis : The treatment of an acute thrombotic event (thrombolysis and/or heparin) . Because of the high risk of recurrence of thrombosis in APS, a strong case can be made for life-long anticoagulation after a first thrombotic event. If anticoagulation is stopped after 6 months,there is a recurrence rate of 20% or more .
Treatment The APS patient with thrombosis and thrombocytopenia is of special concern. Thrombocytopenia does not protect the APS patient from thrombosis. Most thrombocytopenia in APS is mild, in the range of 90 to 140,000. Profound thrombocytopenia, however, would greatly increase the risk of bleeding with anticoagulation. The platelet count should be stable at above 50,000 before chronic anticoagulation is begun, and the INR goal would be 2.0 in such a patient.
Catastrophic AntiphospholipidSyndrome treatement is by heparin, plasmapheresis or intravenousimmunoglobulin, and high dose methylprednisolone(the latter likely calms the cytokine storm producedby the intense endothelial cell activation) . Cyclophosphamide is not recommended as initial therapy because of the increased risk of infection. Mortality of catastrophic APS, even with intensive t reatment in major academic centers, remains 50%. Mortality RATE
Treatments under trials Statins have benefit for APS in animal models andreduce thrombosis in clinical studies of non-APSpatients. However, they cannot be used in pregnancyand have not been studied formally in APS. Rituximab depletes B cells, including B cells that make aPL. However, the period of B-cell depletion is variable, and long-lived plasma cells make aPL survive. Further studies are needed before it can be recommended for APS.
LUPUS AND MATERNAL OUTCOME Coexistence of other medical or obstetrical disorders. Whether there are an APA. About 40% experience flares, relatively mild in the form of artheralgia and rash.
PREGNANCY OUTCOME IS BETTER IF Lupus activity has been quiescent for at least 6 months before conception There is no active renal involvement manifest by Proteinuria or renal dysfunction. Superimposed preeclampsia does not develop. There is no evidence of APA activity.
CONDITIONS THAT SHOULD NOT BE PREGNANT Active Lupus Nephritis, nephrotic syndrome (esp. Cr >2) Other organ damages (e.g. cardio-pulmonary involvement, anemia, thrombocytopenia, CNS involvement, thrombosis) Still take high dose steroid and immunosuppressive drugs
PREPARING FOR PREGNANCY WITH SLE Discuss desire to have child with Rheumatologist, Obstetrician Women with Lupus nephritis are encouraged to delay pregnancy until their disease is inactive for at least 6 months
MEDICATIONS DURING PREGNANCY Drugs to avoid (Immunosuppressant therapy) Mycophenolate mofetil Cyclophosphamide Methotrexate Biologic medications Etanerecpt, infliximab, anakinra Until more data is available, these meds should be avoided Drugs with small risk of harm Aspirin Prednisone/Glucocorticoids Azathioprine NSAIDs Drugs that are probably safe Antimalarials (hydroxychloroquine) No evidence that antimalarials increases risk of miscarriages or birth defects at normal doses
MANAGEMENT DURING PREGNANCY Assessment of severity using SLE-pregnancy disease activity index (SLEPDAI). Serial hematological studies may detect changes in disease activity, hemolysis, anemia, reticulocytosis, thrombocytopenia, leucopenia.
MANAGEMENT DURING PREGNANCY Serum transaminase activity reflects hepatic involvement, as does arise in serum bilirubin. Thrombocytopenia and Proteinuria resemble Lupus disease activity The fetus should be closely observed for adverse effects. Screening for anti SS-A and anti SS-B antibodies, and is found, fetal cardiac function should be evaluated.
RECOMMENDATIONS Delivery: will need stress dose steroid during active labor Breastfeeding: recommended even for women with SLE Birth control: OCP can be used but should be avoided
PHARMACOLOGICAL TREATMENT follow-up frequency is dependent on disease activity hydroxychloroquine is given to prevent flares Low dose aspirin is administered to prevent preeclampsia If APLS positive or history of thrombosis or fetal loss, treatment with heparin or LMWH and aspirin 100 mg per day.
PHARMACOLOGICAL TREATMENT Severe disease is managed with corticosteroid, such as Prednisolone 1 to 2 mg/kg per day. or Chloroquine (250 mg/day) After the disease is controlled, this is tapered to a daily dose of 10 to 15 mg each morning. Corticosteroid therapy can result in the development Gestational or even Type 1 Diabetes.
CORTICOSTEROID In patient with positive anti SSA/Ro or anti SSB antibodies no treatment was administered unless there were intrauterine cardiac complication, in which case Dexamethasone (4 mg/day) was given.
Neonatal Lupus syndrome generalized photosensitive rash thrombocytopenia and anemia giant cell hepatitis with severe cholestasis isolated complete heart block or cardiomyopathy Neonatal Lupus may appear up to 4 weeks after birth.
CONGENITAL HEART BLOCK The consequence of diffuse myocarditis and fibrosis in the region between the Atrioventricular node and Bundle of His CHB occurred almost exclusively in infants of women with antibodies to the SSA/Ro or SSB/La antigen causes unexplained stillbirth, arrhythmia is only 3%. The cardiac lesion is permanent, and pacemaker is generally necessary. Long term prognosis is not good, and 1/3 of affected infants die within 3 years.