Antiphospholipid antibody syndrome an overview

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1 Antiphospholipid antibody syndrome an overview C Sridevi, DNB (Medicine) DNB (Cardiology) MNAMS* P Krishnam Raju, MD DM (Cardiology)* INTRODUCTION Antiphospholipid antibody syndrome (APLAS) was first described to denote a constellation of clinical signs including venous and arterial thrombosis, fetal loss and presence of anticardiolipin antibodies (ACLA). Antiphospholipid antibody syndrome is a form of hypercoagulability disorder. According to Virchow s hypothesis, changes in vessel wall, changes in blood flow or changes in contents of blood cause thrombosis. Various disorders like surgery, immobility, trauma, malignancy, pregnancy are associated with thrombus formation resulting in deep venous thrombosis. Many disorders like protein C deficiency, protein S deficiency, factor V Leiden, antithrombin deficiency are congenital thrombophilias. Acquired defects associated with thrombosis include protein C resistance, antiphospholipid antibody syndrome, oral contraceptives and hormone replacement therapy, polycythemia vera and essential thrombocythemia etc. 1 Antiphospholipid (apl) antibodies are a family of autoantibodies reacting with phospholipids, phospholipid-binding proteins or both. 2,3 These antibodies exhibited an easily detectable biological effect as evidenced by their ability to prolong clotting times of plasma. Antiphospholipid antibodies (APLA) that include ACLA and lupus anticoagulant (LA) are also acquired blood protein defects associated with thrombosis. These are the commonest acquired blood protein defects associated with venous and arterial thrombosis. The individuals with APLAS develop predictable thrombosis episodes more in arterial than venous territories. However, both ACLA and lupus anticoagulant have thrombosis, fetal wastage and thrombocytopenia, lupus anticoagulant has more unpredictable episodes and more venous than arterial thrombosis. Anticardiolipin antibody-associated thrombosis is more common than the LA-associated thrombosis, with a ratio of 5:1. 4 HISTORY In 1906, a complement fixing antibody was described in patients with syphilis. This antibody reacted with extracts from *Consultant Cardiologist, CARE Hospital, Banjara Hills, Hyderabad. Correspondence: Prof. P Krishnam Raju, Cardiologist, CARE Hospital, Banjara hills, Hyderabad (AP). drpkrishnamraju@gmail.com bovine heart relevant antigen, which was later identified as cardiolipin, a mitochondrial phospholipid. This test became the basis for venereal disease research laboratory (VDRL) test done in patients with syphilis. In 1952, mass screening of blood for syphilis led to the finding that many patients with systemic lupus erythematosis (SLE) who did not have clinical or other serological evidence of syphilis were found to have false positive VDRL. This false positivity was due to the presence of an inhibitor, later named lupus anticoagulant (LA). 5 Subsequently in 1960, association of LA with thrombosis was described. In 1975, its association with recurrent thrombosis was noted. In 1983, a solid phase immunoassay was described for detection of ACL antibodies. The association of these antibodies with SLE was described. 6 In 1986, Hughes and his colleagues described the association of the ACL antibodies and recurrent venous and arterial thrombosis, fetal loss and moderate thrombocytopenia; and named this syndrome as antiphospholipid antibody syndrome. 7 Enzyme-linked immunosorbent assay (EL1SA) test was described in 1985 for detection of ACL antibodies. 8 In early 1990, Galli and MacNeil independently discovered that some ACL antibodies require the presence of plasma phospholipid binding protein β-2 glycoprotein 1 (β-2 Gp-I) in order to bind to cardiolipin. 9 This feature is characteristic of patients with SLE or APLAS but is not seen in patients with syphilis or other infectious diseases. Antibodies in these latter groups are not dependent on β-2 Gp-I but are also inhibited by it. Subsequently, it was discovered that phospholipid binding proteins and phospholipids are equally important as some antibodies bind directly to β-2 Gp-I. Antiphospholipid syndrome History 1906 Wasserman reaction 1941 Reagin binds cardiolipin 1952 False-positive test for syphilis 1959 Cofactor requirements for LA activity 1960s LA: association with thrombosis 1970s LA is due to immunoglobulin 1975 LA: association with recurrent abortions 1983 ACLA: detection by radioimmunoassay 1985 ACLA: detection by ELISA 1980s Clinical description of the antiphospholipid syndrome 1987 Diagnostic criteria for the antiphospholipid syndrome 1989 LA and anticardiolipin: separate antibody subgroups 1990 Cofactor requirements for anticardiolipin antibody-binding 1990 Anticardiolipin cofactor: β 2 -glycoprotein I 1991 LA cofactor: prothrombin 1991 Animal models: passive immunization 1992 Animal models: active immunization 1992 LA cofactor: β 2 -glycoprotein I 1992 Anti β 2 -glycoprotein I: association with thrombosis 1994 Phospholipid binding site: fifth domain of β 2 -glycoprotein I 1999 Sapporo International Consensus Statement on Preliminary Criteria for the Classification of the Antiphospholipid Syndrome 2006 International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome JICC Vol 1 Issue ICC

2 Sridevi and Raju IMMUNOLOGY Phospholipids are the basic constituents of cell. Tissue injury due to inflammation, ischemia, trauma, toxins and initiation of programed cell death (apoptosis) leads to exteriorization of these phospholipids. Two types of antibodies that bind to these phospholipids have been widely studied. They are LA and ACL antibodies. The ACL antibodies are immunoglobulins of IgG, IgA and IgM. They react with phospholipids, nucleic acids and glycosaminoglycans. Less well-characterized antiphospholipid antibodies combine with prothrombin, protein C thrombomodulin and phospholipase A2 and are capable of promoting abnormal coagulation. Important antiphospholipid antibodies in thrombosis 10 Lupus anticoagulant (IgG, IgM) Anticardiolipin antibodies (IgG, IgA, IgM) β 2 -glycoprotein I Hexagonal phospholipid Subgroups Anti-phosphatidylserine (IgG, IgA, IgM) Anti-phosphatidylethanolamine (IgG, IgA, IgM) Anti-phosphatidylinositol (IgG, IgA, IgM) Anti-phosphatidylcholine (IgG, IgA, IgM) Anti-phosphatidylglycerol (IgG, IgA, IgM) Anti-phosphatidic acid (IgG, IgA, IgM) Anti-annexin-V antibodies (IgG, IgM) Lupus anticoagulant represents a family of antibodies whose principle targets are plasma proteins. LA is inappropriately named, as they lead to thrombosis and not bleeding. LA inhibits calcium dependent binding of prothrombin and factor Xa to phospholipids and inhibits conversion of prothrombin to thrombin. LA is not directed against a specific antigen but towards a number of phospholipids. It prolongs activated partial thromboplastin time (aptt) but this is not a specific test. In one study, almost 50% of patients are missed for LA by aptt. Platelet neutralizing procedure, kaolin clotting time, and Russell viper venom time are tests to detect LA. Increased levels of IgG ACL, particularly, IgG2 incur greater risk of thrombosis than other immunoglobulins. IgG are most frequently isolated and can be detected by ELISA. IgM antibodies occur less frequently but are also detected by ELISA. 10 Idiotype/isotype distribution in antiphospholipid syndrome 36% have isolated IgG 17% have isolated IgM 14% have isolated IgA 33% have various admixtures Although the LA is associated with thrombosis, the mechanism by which thrombosis occurs is less clear. Proposed mechanism may be interaction with vasculature thereby altering prostaglandin release. There may be activation of platelets and changes in prostaglandin metabolism or antibodies may block protein C or alter phospholipid interaction and activated factor V. There may be hyperactivity of the fibrinolytic system and increased level of plasminogen activator inhibitor. Thrombocytopenia and fetal resorption have been found to occur after passive transport of ACL and active immunization of mice. GENETICS Few patients with some underlying genetic abnormalities (acetylator status, null alleles at C4a and C4b loci and coagulation factor V leiden mutation) develop clinical features while taking drugs that are known to induce APLAS. Families positive for APLAS exist. HLA studies have suggested association with HLA DR4, HLA DR7, HLA DRw53, Dqw7 and APLAS. EPIDEMIOLOGY Anticardiolipins are found among young apparently healthy subjects with a prevalence of 1 5%. The prevalence of APLA increases with age, especially among elderly patients with coexisting chronic diseases. In patients with SLE, the prevalence is much higher for ACL, 12 30% for ACL and 15 30% for LA. Although thrombosis may occur in 50 70% of patients with apl and SLE over a 20-year follow-up period, as many as 30% do not develop antiphospholipid syndrome (APS). 11 Anticardiolipin and LA are also described in association with stroke, myocardial infarction (MI) and fetal loss. Hamstel et al in 1986 described that 21% of young patients with MI had association with APLA positivity. A collaborative UK and Spanish study described, 6.8% of patients with stroke had APLA. APLAS is commonly associated with women presenting with recurrent fetal loss. Lynch et al (1994) in large prospective cohort study of 389 nulliparous mothers assessed at study entry, and at delivery showed that 95 (24%) were positive for APLAS of which 15% had pregnancy loss as compared with 6.5% who were negative for APLAS. The risk of thrombosis in patients with APS is estimated to range from 0.5% to 30%. 12 According to analysis of 1000 patients reported by the multicenter Euro-Phospholipid Project, APS syndrome is more common in women than men in about a 5:1 ratio. 13 In patients with SLE, the male/female ratio is even higher (7:1). Female patients also appear to frequently demonstrate the clinical features of arthritis, livedo reticularis, and migraine, whereas males more often develop MI epilepsy, and lower extremity arterial thrombosis. Although the most common age of onset of the clinical manifestations of APS has a mean of 31 years, the disorder may be seen in children and older patients as well. 13 The specificities of APLA differ with various disorders. Patients with high concentration of IgG are associated with JICC Vol 1 Issue ICC

3 Antiphospholipid antibody syndrome an overview thrombosis whereas risk of clotting appears to be less in patients with infection related or drug-induced APLA. The patients who can be identified as high risk for APLA have important risk factors like history of thrombosis, presence of LA antibodies and persistence of high levels of APLA. Except for the previous thrombotic event, none of the above individual risk factors are sufficiently predictive to warrant treatment. Antiphospholipid antibody can also be associated with nephrotic syndrome, oral contraceptives, stasis and vascular injury. These factors with second hit promote the of thrombosis caused by APLAS. MECHANISM OF THROMBOSIS IN ANTIPHOSPHOLIPID SYNDROME The precise mechanism whereby hemostasis is altered to induce a hypercoagulable state in APS remains unclear. Several mechanisms may be responsible for the clinical manifestations in patients who have APS. Phospholipids are an integral part of platelet and endothelial cell surface membranes. It is expected that anti-phospholipid antibodies would have a significant effect on platelet and vascular endothelial mechanisms. The currently proposed mechanisms of action involve platelet activation, blood coagulation alterations, fibrinolytic deficit, endothelial cell remodeling, or combined effects. 14 Platelet Activation Antibodies to b 2 -glycoprotein I β 2 -glycoprotein I (β 2 -GP I) is an inhibitor of contact activation of the coagulation system. Following platelet activation, phospholipid-binding proteins such as β 2 -GPI interact with the negatively charged phospholipids that are exposed on the surface of the platelet If antibodies to β 2 -GP I are formed, the natural anticoagulant properties of β 2 -GP I are blocked. Complexes of β 2 -GPIphospholipid antibody activate platelets via binding to the FcIIa platelet receptor, causing platelet activation and aggregation. Interaction of Platelets with Endothelial Cells Platelets that have bound APAs alter platelet-endothelial cell interactions Interaction of Platelets with Leukocytes Activated platelets interact with leukocytes. In the presence of APAs, there is increased tissue factor (TF) expression from monocytes Anti-annexin V Antibodies Annexin V is a calcium-dependent vascular anticoagulant protein that binds to phospholipids, preferably phosphatidylserine (PS), on platelet membrane surfaces. Exposure of PS on the cell surfaces produces pro-inflammatory and procoagulant activities. Annexin V binds to PS, thus inhibiting these responses. Anti-annexin V antibodies interfere with the annexin V-induced inhibition of the procoagulant and pro-inflammatory activities of apoptotic cells. 29 High levels of anti-annexin V have been detected in patients who have SLE and APS, and have been associated with an increased risk of thrombosis that leads to recurrent abortions, pre-eclampsia, and fetal death Downregulation of Prostacyclin Prostacyclin is an important inhibitor of platelet activation. APAs impair prostacyclin synthesis in endothelial cells and upregulate the generation of thromboxane, leading to vasoconstriction and platelet aggregation Blood Coagulation Alterations Reduced Activity of Protein C and Protein S Protein C and its cofactor protein S are bound to the thrombinthrombomodulin complex that is bound to a negatively charged phospholipid surface. Because APAs interfere with the binding of the proteins to thrombomodulin, activation of protein C could be inhibited, or the activity of protein C could be inhibited. 36 Interference with Antithrombin III Activity Heparan sulfate on the surface of endothelial cells acts as a natural anticoagulant through binding with antithrombin III (AT). IgG isolated from patients who have APS reacts with a specific disaccharide sequence found in the critical AT-binding region of heparin, heparan sulfate, and other glycosaminoglycans (GAGs). This may reduce the endogenous anticoagulant activity of AT. 37 Upregulation of Tissue Factor Expression Immunoglobulin G from patients who have LA, induce TF activation in endothelial cell culture. The expression of TF on endothelial cells induced by isolated IgG from LA patients has been shown to correlate with clinical thrombosis Fibrinolytic Deficit Binding of APAs to endothelial cells downregulates the expression of tissue plasminogen activator (tpa), leading to a decrease in fibrinolytic activity Interference with Endothelial Cell Phospholipids Endothelial cells are involved in many of the hemostatic mechanisms, either directly or in combination with activated platelets, proteins, receptors, enzymes, and so forth. Potential mechanisms of hemostatic abnormalities associated with endothelial cells in APS (as described above) may be caused by prothrombotic endothelial cells. If β 2 -GPI binds to phospholipid on the vascular endothelial surface, circulating APAs will recognize and bind to the β 2 -GPI phospholipid complex and cause endothelial cell damage. This can result in the exposure of endothelial substances of procoagulant activity such as TF. 14 Platelet-endothelial cell interactions and platelet-leukocyte interactions can be enhanced, augmenting the procoagulant state and establishing a site for thrombus formation. 14 JICC Vol 1 Issue ICC

4 Sridevi and Raju Upregulation of Inflammation Inflammation plays a major role in the pathogenesis of autoimmune diseases. Anti-annexin V antibodies are associated with inflammation and a procoagulant state. 44 It has been shown that endothelial cells are activated by APAs, as demonstrated by an upregulation of the adhesion molecules vascular cell adhesion molecule (VCAM) and E-selectin. 20 In summary, the proposed mechanisms of actions by which APLS interferes with hemostasis resulting in thrombosis are: Reduced endothelial synthesis of prostacyclin Reduced activation of protein C via thrombomodulin/ thrombin or interference with protein S activity, a cofactor to protein C activation Modulation of anticoagulant actions of antithrombin III activity Interaction with platelet membrane phospholipids leading to platelet activation and release Interference with activation of prekallikrein to kallikrein, which in turn activates the fibrinolytic system 45 Reduction of the release of endothelial cell plasminogen activator, thereby producing a fibrinolytic deficit and enhancing the key player of the fibrinolytic system Opposing Effects of Antiphospholipid Antibody on Coagulation Procoagulant effect Inhibition of the activated protein C pathway Upregulation of the tissue factor pathway Disruption of annexin V shield on membranes Inhibition of anticoagulant activity of β 2 -glycoprotein I Inhibition of fibrinolysis Activation of endothelial cells Enhanced expression of adhesion molecules by endothelial cells and adherence of neutrophils and leukocytes to endothelial cells Activation and deregulation of neutrophils and leukocytes to endothelial cells Potentiation of platelet activation Enhanced platelet aggregation Enhanced binding of β 2 -glycoprotein I to membranes Enhanced binding or prothrombin to membranes Anticoagulant effect Inhibition of activation of factor IX Inhibition of activation of factor X Inhibition of activation of prothrombin to thrombin Inhibition of antithrombin III activity PRIMARY VERSUS SECONDARY ANTIPHOSPHOLIPID SYNDROME Primary APLAS has generally been defined as the presence of apl in patients with idiopathic thrombosis but no evidence of autoimmune disease or other inciting factor, such as infection, malignancy, hemodialysis or drug-induced apl. 47 The term secondary APLAS has been used when patients with a wide spectrum of autoimmune disorders (primarily systemic lupus erythematosus [SLE] and rheumatoid arthritis); and thrombosis are also found to have apl. 48,49 The clinical manifestations of thrombosis are similar, whether the APS is primary or secondary, and the 2006 International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome eliminated the primary versus secondary distinction. 3,50 52 In replacing this primary versus secondary designation, the 2006 criteria designates two subgroups of APS patients those with and those without the presence of other risk factors for arterial or venous thrombosis. 53 Clinical Manifestations of Antiphospholipid Syndrome 46 Thrombosis of Large Vessels Neurologic: transient ischemic attack, ischemic stroke, chorea, seizures, dementia, transverse myelitis, encephalopathy, migraines, pseudo-tumor cerebri, cerebral venous thrombosis, mononeuritis multiplex Ophthalmic: retinal vein and/or artery thrombosis, amaurosis fugax Cutaneous: superficial phlebitis, leg ulcers, distal ischemia, blue toe syndrome Cardiac: myocardial infarction, valvular vegetations, intracardiac thrombi, atherosclerosis Pulmonary: pulmonary emboli, pulmonary hypertension, pulmonary arterial thrombosis, alveolar hemorrhage Arterial: thrombosis of aorta, thrombosis of large and small arteries Renal: renal vein/artery thrombosis, renal infarction, acute renal failure, proteinuria, hematuria, nephrotic syndrome Gastrointestinal: Budd-chiari syndrome, hepatic infarction, gallbladder infarction, intestinal infarction, splenic infarction, pancreatitis, ascites, esophageal perforation, ischemic colitis Endocrine: adrenal infarction or failure, testicular infarction, prostate infarction, pituitary infarction, pituitary failure Venous thrombosis: thrombosis in extremities, adrenal thrombosis, hepatic thrombosis, mesenteric thrombosis, thrombosis in splenic veins, vena cava thrombosis Obstetrical complications: pregnancy loss, intrauterine growth retardation, hemolytic anemia, elevated liver enzymes, and low platelet count (HELLP) syndrome, oligohydraminos, pre-eclampsia Hematologic: thrombocytopenia, hemolytic anemia, hemolyticuremic syndrome, thrombotic thrombocytopenic purpura Miscellaneous: perforation of the nasal septum, avascular necrosis of bone Microvascular thrombosis Ophthalmic: retinitis Cutaneous: livedo reticularis, superficial gangrene, purpura, ecchymoses, subcutaneous nodules JICC Vol 1 Issue ICC

5 Antiphospholipid antibody syndrome an overview CLINICAL SPECTRUM OF ANTIPHOSPHOLIPID ANTIBODY SYNDROME 46 apl absent apl absent Asymptomatic No thrombosis Autoimmune disease & apl Asymptomatic apl No thrombosis or micro thrombosis Pre-probable APS Drug-induced apl (thrombosis less common) Infection-induced apl (thrombosis less common) Thrombosis present Seronegative APS (SNAPS) Definite APS (without SLE- Primary ) APS (without SLE- Secondary ) Microangiopathic APS apl: antiphospholipid APS: antiphospholipid syndrome Catastrophic APS (CAPS) Life-threatening thrombosis Cardiac: myocardial infarction, myocardial microthrombi, myocarditis, valvular abnormalities Pulmonary: acute respiratory distress syndrome, alveolar hemorrhage Renal: acute renal failure, thrombotic microangiopathy, hypertension Gastrointestinal: intestinal, hepatic, and splenic infarctions or gangrene Hematologic: disseminated intravascular coagulation (only in CAPS) Miscellaneous: microthrombi, microinfarctions A typical set of clinical manifestations with or without positive serologic tests for apl, but not qualifying as definite APS, has been described as probable APS or pre-aps. 54 A new subset of APS has been proposed, defined as microangiopathic APS. 54,55 The 2006 criteria also identifies patients with typical manifestations of APS but negative apl serologies (seronegative APS [SNAP]), 56 occurs in patients with Sneddon s syndrome (the clinical triad of stroke, livedo reticularis, and hypertension). 57 Types of Antiphospholipid Thrombosis Syndromes Type I Syndrome Deep venous thrombosis with or without pulmonary embolus Type II Syndrome Coronary artery thrombosis Peripheral artery thrombosis Aortic thrombosis Carotid artery thrombosis Type III Syndrome Retinal artery thrombosis Retinal vein thrombosis Cerebrovascular thrombosis Transient ischemic attacks (TIAs) Type IV Syndrome Mixtures of types I, II, and III; type IV patients are rare Type V (Fetal Wastage) Syndrome Placental vascular thrombosis Fetal wastage common in first trimester Fetal wastage can occur in second and third trimesters; maternal thrombocytopenia (uncommon) Type VI Syndrome Antiphospholipid antibody with no apparent clinical manifestations TYPES OF ANTIPHOSPHOLIPID THROMBOSIS SYNDROMES The antiphospholipid thrombosis syndrome, associated with anticardiolipin (ACL) or subgroup antibodies can be divided into one of six subgroups : There is little overlap (about 10% or less) between these subtypes, and patients usually conveniently fit into only one of these clinical types, most patients fitting into one of the first three types. Although there appears to be no correlation with the type, or titer, of ACL antibody and type of syndrome (I VI), the JICC Vol 1 Issue ICC

6 Sridevi and Raju subclassification of thrombosis and ACL antibody patients into these groups is important from the therapy standpoint. Asymptomatic Antiphospholipid Antibodies Why some individuals develop, thrombosis and some do not also remains poorly understood. While apl may be present as a predisposing risk factor, the addition of a triggering risk factor, or double hit, may be required for the development of thrombosis. 49 Identifiable risk factors for transition from asymptomatic apl to APS (apl with thrombosis) include a prior history of thrombosis, 62,63 the presence of lupus anticoagulant, 64 and an elevated level of ACL IgG. 47,65,66 Various reports suggest that each of these risk factors increase the risk of thrombosis to about fivefolds. 67 Recent analysis of the warfarin anti-phospholipid syndrome study by Galli confirms that the association between lupus anticoagulant, β2- GPI antibodies, antiprothrombin antibodies, and anti annexin V antibodies with thrombosis is stronger than the association between other apl and thrombosis. 68 Probable Antiphospholipid Syndrome Many patients, positive for apl exhibit clinical features suggestive of APS but lack criteria of vascular thrombosis or pregnancy loss necessary to substantiate a diagnosis of definite APS. Such patients have been classified as probable APS or pre-aps. 54 Clinical manifestations include livedo reticularis, chorea, thrombocytopenia, fetal loss, and cardiac valvular lesions. 69 Seronegative Antiphospholipid Syndrome A subset of patients has been identified who exhibit clinical manifestations of APS, without identifiable apl, lupus anticoagulant, β2-gpi, antiphospholipid subtype antibodies, or any other recognized apl on laboratory testing. These individuals are said to have SNAP syndrome. 56 Such patients develop idiopathic arterial or venous thrombosis and initial testing for apl is negative. Repeat testing months later may return positive. 70 Definite Antiphospholipid Syndrome The 1999 Sapporo International Consensus Statement on Preliminary Criteria for the Classification of the Antiphospholipid Syndrome defined patients with primary APS as those with both clinical and laboratory criteria for the diagnosis in the absence of defined connective tissue disease, and patients with secondary APS as those with APS and the presence of connective tissue disease. The 2006 International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome eliminates this distinction. For a definite diagnosis, patients must have one or more clinical episodes of arterial, venous, or small-vessel thrombosis occurring within any tissue or organ. Thrombosis may include the placenta and result in fetal death or premature birth. Many clinical disorders are associated with the presence of apl, but not rising to the level of evidence necessary to be included in the 2006 Consensus Statement. 53 Laboratory criterion are well defined and require ACL IgG, or IgM, or lupus anticoagulant in high titers (> 40 IgG phospholipid units [GPL] or IgM phospholipid units [MPL] or > 99th percentile); confirmed on repeat testing 12 weeks later 53,71,72 not included in the 1999 International Criteria, but included in the 2006 International Criteria are IgG and IgM antibodies to β 2 -GpI, which are also highly predictive of risk for thrombosis. 51,53 Not included in either criterion are antibodies to the antiphospholipid subtypes, anti-prothrombin or anti annexin V, which have also been linked to risk for thrombotic events. 68,73 79 Revised Classification Criteria for Antiphospholipid Syndrome 46 Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the laboratory criteria that follow, are met.* Clinical Criteria 1. Vascular thrombosis**one or more clinical episodes of arterial, venous, or small-vessel thrombosis, occurring in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. 2. Pregnancy morbidity (a) One or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation, documented by ultrasound or by direct examination of the fetus, or (b) One or more premature births of morphologically normal neonates 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) Three 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. In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to *, ** or above. Laboratory Criteria f 1. Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis (Scientific Subcommittee on LAs/phospholipid- dependent Antibodies). 2. Anticardiolipin of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (> 40 IgG phospholipid units [GPL] or IgM phospholipid units [MPL], or > 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA. 3. Anti-β 2 -GpI IgG and/or IgM isotype in serum or plasma (in titer > 99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures. *Classification of APS should be avoided if < 12 weeks or > 5 years separate the positive apl test and the clinical manifestation. JICC Vol 1 Issue ICC

7 Antiphospholipid antibody syndrome an overview **Coexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two subgroups of APS patients should be recognized, according to (a) the presence, and (b) the absence of additional risk factors for thrombosis. Indicative (but not exhaustive) of such cases include age (> 55 years in men and > 65 years in women), and the presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated low-density lipoprotein or low high-density lipoprotein cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index > 30 Kg/m 2, microalbuminuria, estimated glomerular filtration rate < 60 ml/min), inherited thrombophilias, oral contraceptives, nephrotic syndrome, malignancy, immobilization, and surgery. Thus, patients who fulfill criteria should be stratified according to contributing causes of thrombosis. A thrombotic episode in the past could be considered as a clinical criterion; if thrombosis is proved by appropriate diagnostic means and that, no alternative diagnosis or cause of thrombosis is found. Superficial venous thrombosis is not included in the clinical criteria. # Generally accepted features of placental insufficiency include (i) abnormal or non-reassuring fetal surveillance test(s) (e.g., a non-reactive non-stress test suggestive of fetal hypoxemia), (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia (e.g., absent end-diastolic flow in the umbilical artery), (iii) oligohydraminos (e.g., an amniotic fluid index of 5 cm or less), or (iv) a postnatal birth weight less than the 10th percentile for the gestational age. f Investigators are strongly advised to classify APS patients in studies into one of the following categories: I, more than one-laboratory criteria present (any combination); IIa, lupus anticoagulant present alone; IIb, acl present alone; IIc, anti-β-2-gp I present alone. Microangiopathic Antiphospholipid Syndrome Patients with APS may present with a variety of disorders characteristic of microvascular occlusive disease. Such disorders include thrombotic thrombocytopenic purpura (TTP), hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, thrombotic microangiopathic hemolytic anemia, and CAPS (Asherson s syndrome). Syndromes may also exhibit overlapping features characteristic of more than one of these conditions. All share the pathologic features of microangiopathy. 54 Drug-induced Antiphospholipid Syndrome Varieties of medications have been documented to induce the formation of apl. These have included chlorpromazine, phenytoin, hydralazine, rocainamide, fansidar, quinidine, interferon, and cocaine. Most apl is of the IgM type; present at low levels, and not associated with an increased incidence of thrombosis. 80 Infection-associated Antiphospholipid Syndrome A variety of infectious agents triggers the production of apl. 81 Antibodies induced by infection recognize anionic phospholipid epitopes directly rather than via cofactors such as β2-gpi. Autoantibodies are more often IgM than IgG. The clinical features typical of APS are less commonly observed with apl associated with infections. 81 Some infections, however, have been well documented to be associated with the development of apl and β 2 -GPI and are thus more likely to be associated with the subsequent development of thrombosis (leprosy, parvovirus B19, HIV, hepatitis C virus, cytomegalovirus). 81 Infection may be the triggering factor in as many as 40% of cases of CAPS. 82 Malignancy-associated Antiphospholipid Syndrome Varieties of solid and hematologic malignancies have been reported to be associated with the presence of apl. The relationship between malignancy, the development of apl, and thrombosis is poorly understood. 83 Catastrophic Antiphospholipid Syndrome Catastrophic antiphospholipid syndrome (CAPS), a syndrome of multisystem involvement as a manifestation of APS, was first described by Asherson. 84 The syndrome was coined Asherson s syndrome in Occurring in fewer than 1% of APS patients, the syndrome is characterized by multiple small-vessel occlusions leading to multiple organ failure and substantial morbidity and mortality. 86 The syndrome is generally of acute onset and defined by the involvement of at least three different organ systems over a period of days or weeks. Histopathologically, there is evidence of small- and large-vessel occlusions. The striking feature of the syndrome is the presence of an acute microangiopathy, rather than the large-vessel occlusions more typically observed in patients with both primary and secondary APS. 82 Clinical features are the manifestations of organ and tissue ischemia, and include renal failure due to renal thrombotic microangiopathy, acute respiratory failure due to adult respiratory distress syndrome, cerebral injury due to microthrombi and micro-infarctions, and myocardial failure due to microthrombi A review by Asherson and Cervena in noted that infection triggered CAPS in as many as 40% of patients with CAPS. An initial thrombosis, felt to be a typical acute thrombosis in a patient with APS, may rapidly evolve into the systemic microangiopathy, described by Kirchens as a thrombotic storm. 89 The 2002 International Taormina Consensus Statement on Classification and Treatment of CAPS 87 proposed international preliminary CAPS classification criteria and treatment guidelines. Preliminary Criteria for the Classification of Catastrophic Antiphospholipid Syndrome* 1. Evidence of involvement of 3 organs, systems, and/or tissues** 2. Development of manifestations simultaneously or in < 1 week 3. Confirmation by histopathology of small-vessel occlusion in atleast one organ/tissue**, 4. Laboratory confirmation of the presence of apl (lupus anticoagulant and/or acl an/or anti-β 2 -GPI) Definite CAPS all four criteria Probable CAPS Criteria 2, 3, and 4, plus evidence of involvement of only two organs, systems, and/or tissues All four criteria, except for the absence of laboratory confirmation of the presence of apl at least 6 weeks after a first positive result (because of the early death of a patient never tested for apl before onset of CAPS) (Contd) JICC Vol 1 Issue ICC

8 Sridevi and Raju Probable CAPS (Continued) Criteria 1, 2, and 4 Criteria 1, 3, and 4, plus the development of a third event in > 1 week but < 1 month, despite anticoagulation treatment *Proposed and accepted during the 10th International Congress on Antiphospholipid Antibodies (apl), September **Usually clinical evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension (> 180/100 mmhg), and/or proteinuria (> 500 mg/24 h). For histopathologic confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally. If the patient had not been previously diagnosed as having APS, the laboratory confirmation requires detection of the presence of apl on two or more occasions atleast 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of definite APS. identified risk factors for atherosclerosis. This primarily includes individuals under age 60, without classical risk factors for atherosclerosis (family history, cigarette smoking, hyperlipidemia, hypertension, diabetes mellitus). The presence of ACL is considered a risk factor for first stroke. 99 Arterial thrombosis in patients with APS may also involve other large and small vessels, which is somewhat unusual for other thrombophilic disorders or atherosclerotic occlusive disease. These potential arterial thromboses include thromboses of brachial and subclavian arteries, axillary artery (aortic arch syndrome), aorta, iliac, femoral, renal, mesenteric, retinal, and other peripheral arteries (Figure 1). 11,49,97 CARDIOVASCULAR MANIFESTATIONS OF THE ANTIPHOSPHOLIPID SYNDROME VENOUS THROMBOSIS Venous thrombosis typically presents with deep vein thrombosis (DVT) in the lower extremities. More than half of the patients with symptomatic DVT have asymptomatic pulmonary embolism. No particular clinical pattern of venous thrombosis suggests that the patient may have underlying apl. Unusual sites of venous thrombosis have included the upper extremities, intracranial veins, inferior and superior vena cava, hepatic veins (Budd-chiari syndrome), portal vein, renal vein, and retinal vein. 80,90,91 Thrombosis of the cerebral veins may present with acute cerebral infarction. 92 The superficial and deep cerebral venous system may be extensively involved. Onset of cerebral venous thrombosis caused by apl typically presents at a younger age and in a more extensive pattern than onset of cerebral venous thrombosis because of other reasons. Thrombosis of the superior saggital sinus has also been reported. 93 In the setting of idiopathic venous thromboembolism, laboratory assessment is recommended to search for the presence of underlying thrombophilia. Testing for apl is strongly recommended because of the high frequency with which APS is diagnosed. 94 Even in patients with a family history of venous thrombosis, which suggests an underlying inherited thrombophilic disorder, testing for apl is indicated because many patients with one thrombophilic disorder also have another. 95,96 ARTERIAL THROMBOSIS Arterial thromboses are less common than venous thromboses and occur in a variety of settings in patients with primary APS. 50,97,98 Of the 1000 patients in the Euro-Phospholipid Trial, 13.1% presented with stroke, 7% with transient ischemic attack, and 2.8% with acute MI. 12 Patients with arterial thrombosis most commonly present with TIA or stroke (50%) or MI (23%). 12,90,97 These relatively common arterial occlusive events suggest APS when they occur in individuals without readily Antiphospholipid antibodies are associated with a spectrum of cardiovascular manifestations including accelerated atherosclerosis, valvular heart disease, intracardiac thrombi, myocardial and pericardial involvement, premature vein graft restenosis, and peripheral vascular disease Cardiovascular Manifestations of the Antiphospholipid Syndrome 104 Coronary artery disease Accelerated atherosclerosis Myocardial infarction (MI) Bypass graft failure Stent thrombosis Valvular disease Nonbacterial vegetations Valvular fibrosis and thickening Valvular regurgitation Cerebral and peripheral arterial occlusion Cardiogenic embolism Atherothrombosis in situ Paradoxical embolism Myocardial dysfunction Diffuse cardiomyopathy Diastolic dysfunction Intracardiac thrombosis Pulmonary hypertension Definition of Antiphospholipid-associated Cardiac Valve Disease 105 Antiphospholipid-associated cardiac valve disease is: Coexistence of apl (laboratory criteria for APS) along with Echocardiographic detection of lesions, and/or Regurgitation*, and/or stenosis of mitral, and/or aortic valve or any combination of the above. Valve examination can be performed with TTE and/or with TEE Defining valve lesions include: Valve thickness > 3 mm Localized thickening involving the leaflet s proximal or middle portion Irregular nodules on the atrial face of the edge of the mitral valve, and/or the vascular face of the aortic valve. The presence and severity of regurgitation and/or stenosis should be documented with Doppler echocardiography Two expert echocardiographers should carry out interpretation JICC Vol 1 Issue ICC

9 Antiphospholipid antibody syndrome an overview Both functional capacity and objective assessment of heart status should be reported according to the revised NYHA Criteria for Diagnosis of Heart Disease 106 Confirmation of valve disease may also be provided by histopathological findings of Libman-Sacks endocarditis in patients with concomitant SLE 107 In all the above cases, the presence or history of rheumatic fever and infective endocarditis must be excluded. Patients who fulfill clinical criteria for APS are excluded from the definition above. Researchers should also state if the patient meets, the American College of Rheumatology (ACR) revised criteria for SLE 108,109 *Investigators are advised to consider moderate severe mitral valve regurgitation as criterion for apl-associated cardiac valve disease, as mild regurgitation is very common in the general population. CORONARY ARTERY DISEASE IN ANTIPHOSPHOLIPID SYNDROME Association of antiphospholipid antibodies and atherosclerosis has been established. The prothrombotic state of APS has been implicated in the pathogenesis of premature atherosclerosis in afflicted patients. 110 Studies of arterial intima-media thickness (IMT) using B-mode ultrasound in patients with APS have provided evidence for the atherogenic role of these antibodies. 111 There is some evidence that not all types of apl are equal in regards to their potential contribution to thrombosis and atherogenesis. In a study, Soltesz et al 112 identified differences in the clinical events associated with various types of apl. Specifically, venous thrombosis occurred more frequently in patients who had lupus anticoagulant, while coronary, carotid, and peripheral artery thrombosis occurred more frequently in subjects who had IgG or IgM acl. These findings support the association of apl, specifically antibodies to cardiolipin and its cofactor, β 2 -GPI, with the initiation of atherosclerosis. 104 MYOCARDIAL INFARCTION Several studies have reported elevated levels of anti-cardiolipin antibodies in young patients who had survived a MI and a higher rate of subsequent cardiovascular events occurred in these patients BYPASS GRAFT FAILURE AND STENT THROMBOSIS Antiphospholipid antibodies have been implicated in premature restenosis of vein grafts used in coronary artery bypass surgery (CABG). In a study, Morton et al 117 found a direct correlation between the pre-operative antibody level and the incidence of late graft occlusion in terms of both the number of patients with an occlusion and the number of distal anastomotic occlusions. In another study, Bick et al 118 reviewed patients who had early failure of CABG, percutaneous transluminal coronary angioplasty (PTCA), or both. They found that 30% of patients were positive for either lupus anticoagulant or ACL. Many studies have reported cases of acute stent thrombosis, recurrent stent thrombosis (Muir et al), subacute stent thrombosis (Weissman and Coplan) in patients with APS, despite 100% compliance with antiplatelet medications. 119,120 VALVE ABNORMALITIES AND PERIPHERAL EMBOLIZATION Association of Antiphospholipid Syndrome and Valve Disease Valvular disease was the earliest reported cardiac manifestation of APS. 101 The valvular lesions found in APS are essentially the same entity as SLE-associated Libman-Sacks endocarditis, which classically has been described as verrucous endocarditis of valve leaflets, papillary muscles, and the myocardium. 121 The association of apl with valvular lesions first was recognized in case reports describing nonbacterial vegetations involving the mitral valve in association with cerebral ischemic events in patients who had lupus anticoagulants It is now known that one-third to one-half of patients with primary APS have valve disease, and although it is usually asymptomatic, it can lead to significant mitral and/or aortic regurgitation In addition to valvular thickening and nonbacterial vegetations, actual thrombus formation has been reported on both native and prosthetic heart valves in patients who have APS (Figure 2). 128 The prevalence of apl in patients who have SLE and heart valve disease has been studied extensively. Leung and colleagues 131 studied 75 patients who had SLE and found that ACL was positive in 23 patients, 16 of whom had echocardiographic abnormalities including verrucous valvular thickening and dysfunction. These abnormalities were statistically more common in apl-positive patients than in patients without the antibodies. An European multicenter case-controlled study including 132 patients who had SLE, found the prevalence of valvular lesions in SLE was 22.7% compared with 2.9% in a group of healthy controls. Fifty of the SLE patients were apl-positive, and the prevalence of valve vegetations was significantly higher than in apl-negative SLE patients (16% vs 1.2%, respectively). Mitral regurgitation was present in 38% of apl-positive patients compared with 12% of patients without apl, also a statistically significant difference. 132 Primary APS also has been implicated in the development of heart valve disease. Brenner and colleagues performed echocardiograms on 34 patients who had increased levels of serum ACL antibodies with no evidence of malignancy or SLE. They found valvular lesions in 11 of 34 patients (32%), and the lesions were similar to those observed in SLE patients. 133 The histopathology of apl-associated valve lesions can show fibrosis, calcification, verrucous superficial thrombosis, intravalvular capillary thrombosis, and vascular proliferation. 125,126 JICC Vol 1 Issue ICC

10 Sridevi and Raju Thromboembolic Events in Antiphospholipid Antibodyassociated Valve Disease Antiphospholipids are associated with cerebrovascular occlusions in patients who have SLE and in those who have primary APS. APS theoretically can cause cerebral infarction by several mechanisms. These include cardiogenic embolism from nonbacterial vegetations, in situ atherothrombosis by means of endothelial injury of cerebral arteries, and paradoxical embolism of thrombus across the interatrial septum. 134 MYOCARDIAL INVOLVEMENT IN ANTIPHOSPHOLIPID SYNDROME Diffuse Cardiomyopathy Among patients who have SLE, there is some evidence that primary myocardial failure may be caused by myocarditis associated with antibodies to ribonucleoproteins and skeletal muscle myositis. 135 There is also evidence suggesting that apl may play a role in the development of cardiomyopathy in patients who have no other obvious cause such as coronary or valvular disease. In a study of 75 SLE patients, Leung and colleagues 131 found elevated apl levels in four out of five patients who had isolated left ventricular systolic dysfunction. Several case reports have demonstrated a possible histopathological explanation for diffuse cardiomyopathy in patients who have apl. Murphy and Leach 136 described a 33-year-old man with primary APS who died of heart failure. At autopsy, his heart showed widespread thrombosis within the small intramyocardial arterioles, without evidence of vasculitis. In similar cases, Brown et al 137 and Kaplan et al 101 reported autopsy findings of occlusive microthrombosis of the small arterioles of the heart and other organs. In these cases, there were areas of microinfarction surrounding the affected arterioles, leading to extensive myocardial necrosis. The authors concluded that these findings broaden the spectrum of aplassociated thrombosis to include small arterioles within the heart. The lack of vasculitic changes on histopathological examination supports the notion of a direct thrombotic effect of apl rather than a defect in the vessel wall itself. 104 DIASTOLIC DYSFUNCTION Figure 1 Arterial thrombosis resulting in ischemia and necrosis of the foot. 100 In addition to diffuse cardiomyopathy causing systolic dysfunction, apls have been implicated in primary diastolic dysfunction. It is unclear how apl might cause impaired diastolic function directly, but diastolic dysfunction frequently precedes systolic failure in other disease states. One therefore could conclude that the abnormal left ventricular filling pattern seen in patients who have APS may be an early manifestation of myocardial involvement. 104,138 Vegetations Figure 2 Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows. 129,130 JICC Vol 1 Issue ICC 04-JICC-ATT indd 88 9/8/2011 7:06:24 PM

11 Antiphospholipid antibody syndrome an overview INTRACARDIAC THROMBOSIS Thrombus formation on the endocardial surface is a rare but important cardiac manifestation of apl. Reports of primary intracardiac mural thrombi occurring in all four heart chambers have been published. 101, PULMONARY HYPERTENSION Among patients who have SLE, the prevalence of clinically evident pulmonary hypertension (PHT) is 1% to 14%. 142 In lupus patients, PHT often occurs in the setting of pulmonary vasculitis and/or interstitial lung disease that may lead to elevated pulmonary vascular resistance. 143 Alternatively, SLE-associated apl may play a role in the development of PHT. 144 The mechanism by which circulating apl may lead to PHT is assumed recurrent pulmonary embolism, or chronic thromboembolic PHT. 143 Patients who have primary APS also can develop a broad spectrum of pulmonary complications, the most common of which are pulmonary thromboembolism and PHT. Microvascular pulmonary thrombosis, pulmonary capillaritis, and alveolar hemorrhage also have been reported in patients who have APS. Among medical patients with chronic thromboembolic PHT, the prevalence of apl varies between 10% and 50%. 145 multiple-infarct dementia. 11 Typical APS patients with stroke are relatively young and lack other classical risk factors of stroke. 146 Chorea has been strongly linked to the presence of apl. About 4% of patients with SLE exhibit chorea, which mimics that seen with rheumatic fever (Sydenham s) or Huntington s chorea. Chorea may predate the development of apl and may be followed by acute cerebral ischemia. Other central nervous system manifestations associated with apl include migraine headache, Sneddon s syndrome, seizures, transverse myelitis, Guillain Barré syndrome, idiopathic intracranial hypertension, cognitive dysfunction, psychosis, and optic neuritis. 147 NEUROLOGIC DISORDERS Primary thrombosis and embolic occlusion of cerebral arteries result in cerebral infarction. Most arterial occlusions are of small arteries. Recurrent small strokes may contribute to a picture of Figure 3 Livedo reticularis. 92 Annexure 1 Treatment of antiphospholipid antibody in pregnancy. Antiphospholipid syndrome without previous thrombosis and recurrent early (pre-embryonic or embryonic) miscarriage Antiphospholipid syndrome without previous thrombosis and fetal death (more than 10 weeks geatation) or previous early delivery (< 34 weeks gestation) due to severe pre-eclampsia or placental insufficiency Antiphospholipid syndrome with thrombosis Regimen Low-dose aspirin alone or together with either unfractionated heparin ( IU subcutaneously every 12 h) or LMWH (usual prophylatic doses) Low-dose aspirin plus: Unfractionated heparin ( IU subcutaneously every 12h in the first trimester; U subcutaneously every 12 h in the second and third trimesters, on every 8 12h adjusted to maintain the mid-interval aptt* 1 5 times the control mean) LMWH (usual prophylatic doses) Low-dose aspirin plus: Unfractionated heparin (subcutaneously every 8 12 h adjusted to maintain the mid-interval aptt* or heparin concentration (anti-xa activity)* in the theraputic range) LMWH (usual therapeutic dose eg, enoxaparin 1 mg/kg subcutaneously, or dalteparin 100 U/Kg subcutaneously every 12 h, or enoxaparin 1.5 mg/kg/day subcutanously, or dalteparin 200 U/Kg/day subcutaneously) aptt: activated partial thromboplastin time; LMWH: low-molecular-weight heparin. *Women without a lupus anticoagulant in whom the aptt is normal can be monitored with the aptt. Women with lupus anticoagulant should be monitored with antifactor Xa activity. Need for dose adjustments over the course of pregnancy remains controversial. 99 Some experts argue that in the absence of better evidence, it is prudent to monitor anti-factor Xa LMWH concentrations 4 6 h after injection with dose adjustment to maintain a therapeutic antifactor Xa concentration (0.6 to 1.0 U/mL if a twice-daily regimen is used; slightly higher if a once-daily regimen is chosen). JICC Vol 1 Issue ICC