Laboratory studies on pathophysiology of the catastrophic antiphospholipid syndrome

The 'catastrophic' variant of the antiphospholipid syndrome (APS) is characterized by a diffuse thrombotic microvasculopathy. In contrast to the classical APS, single venous or arterial medium-to-large blood vessel occlusions are uncommon. The mechanisms of catastrophic APS are not clearly understood. In addition, there are no studies on pathophysiologic mechanisms of catastrophic APS. The clinical manifestations of catastrophic APS probably depend on (a) the organs affected by the thrombotic events and extent of the thrombosis and (b) manifestations of the systemic inflammatory response syndrome which are presumed to be due to excessive cytokine release from affected and necrotic tissues. The evident relationship between APS and infection may enable us to explain the development of catastrophic APS using the sepsis model. This is because catastrophic APS is characterized by multiple microvascular thrombotic events, of rapid onset, and causing multiorgan failure, a picture suggestive of septic shock, in which, there is a massive, acute inflammatory response.     

Laboratory evaluation of the adrenogenital syndrome

The adrenogenital syndrome is a result of the deficiency of one of the enzymes involved in the pathway leading to the synthesis of cortisol by the adrenal cortex. Laboratory evaluation of the adrenogenital syndrome involves measurement of hormones and metabolites accumulated prior to the enzymic block as well as hormones whose synthesis is affected by deficiency of a specific enzyme. Laboratory measurements of hormone metabolites in urine, because of their nonspecificity, lack of sensitivity, and multiple assay steps resulting in poor yield, have been supplanted by specific and sensitive radioimmunoassays of steroid hormones in plasma. In the laboratory evaluation of the adrenogenital syndrome, problems involved in some of the immunoassays of selected hormones should be addressed. Variables owing to specimen collection, storage and handling, and the assay itself should be minimized and controlled.     

Diagnostic performance of phospholipid-specific assays for the evaluation of antiphospholipid syndrome

The diagnostic performance of commercially available nonstandard antiphospholipid (aPL) assays for the evaluation of antiphospholipid syndrome (APS) is unknown. In 62 patients with APS, 88 with recurrent pregnancy loss, 50 healthy blood donors, and 24 women with one or more successful pregnancies, we measured antiphosphatidic acid (aPA), antiphosphatidyl-choline (aPC), antiphosphatidylethanolamine (aPE), antiphosphatidylglycerol (aPG), antiphosphatidylinositol (aPI), and antiphosphatidyl-serine (aPS) IgG and IgM antibodies from 2 manufacturers. We computed the areas under the curve (AUC), sensitivities, specificities, positive and negative predictive values, and 95% confidence intervals to assess diagnostic performance. The AUC analyses of the IgM assays demonstrated significant differences (P < .01) for all markers except aPC, whereas the IgG markers showed comparable performance for most assays with the exception of aPE (P < .01) and aPS (P = .02) antibodies. Overall, the combined sensitivity of the aPL assays differed significantly between manufacturers and did not improve the diagnostic yield for APS.     

Obstetric antiphospholipid syndrome

Antiphospholipid syndrome (APS) in pregnancy has a serious impact on maternal and fetal morbidity. It causes recurrent pregnancy miscarriage and it is associated with other adverse obstetric findings like preterm delivery, intrauterine growth restriction, preeclampsia, HELLP syndrome and others. The 2006 revised criteria, which is still valid, is used for APS classification. Epidemiology of obstetric APS varies from one population group to another largely due to different inclusion criteria and lack of standardization of antibody detection methods. Treatment is still controversial. This topic should include a multidisciplinary team and should be individualized. Success here is based on strict control and monitoring throughout pregnancy and even in the preconception and postpartum periods. Further research in this field and unification of criteria are required to yield better therapeutic strategies in the future.     

The antiphospholipid syndrome

Summary Much more is known about the APLS than 15 yr ago, but more needs to be done. Clinically, major characteristics of the disorder have been defined, but the course of the disease and its relationship to other disorders, such as systemic lupus erythematosus (SLE), need to be defined. Good progress has been made in standardizing anticardiolipin and, to a lesser extent, LA. However, problems with interlaboratory and inter-assay variation need to be addressed. Doctors are getting a better idea of how to manage these patients with a view to preventing recurrences of thrombosis or pregnancy losses, but prospective studies are still desirable to give more definitive answers. Attention has turned to the pathogenesis of the disorder. It seems likely that antibodies mediate the clinical disorders with which they are associated, but the mechanisms by which this occurs still require further study.     

Catastrophic antiphospholipid syndrome

The catastrophic antiphospholipid syndrome is a potentially life-threatening condition with a high mortality, which requires a high degree of clinical awareness on the part of attending physicians. Patients with this syndrome have in common: a) clinical evidence of multiple organ involvement developed over a very short time period; b) histopathological evidence of multiple small vessel occlusions, and c) laboratory confirmation of the presence of antiphospholipid antibodies, usually in high titre. The combination of high doses of intravenous (iv) heparin, iv steroids, iv gamma globulins and/or repeated plasma exchanges is the basic treatment of choice for all patients with this severe condition.     

Apoptosis and the antiphospholipid syndrome

The target of many antiphospholipid autoantibodies (APA) has been shown to be a complex between anionic phospholipid (PL) and the plasma protein beta 2-glycoprotein I (beta 2-GPI), but the identity of the natural target(s) and/or immunogen for APA in vivo remains undetermined. The anionic PL of cell membranes represent important potential targets and immunogenes for APA. Although anionic PL are normally absent from the extracellular surface of cell membranes, they redistribute from the inner to the outer leaflet during apoptosis. We and others have shown that beta 2-GPI binds selectively to the surface of apoptotic, but not viable, cells, and that the binding of beta 2-GPI to the surface of apoptotic cells generates an epitope recognized by APA from patients with both primary antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). In this review, we discuss recent findings, which suggest not only that apoptotic cell-bound beta 2-GPI is injected by non-intravenous routes. We also review briefly the potential role of oxidation in generating epitopes responsible for the recognition and induction of APA. Taken together, we believe that the available evidence supports a role for apoptotic cells as far as targets of APA and possible players in the induction of APA.     

Epidemiology of the antiphospholipid antibody syndrome

The prevalence of antiphospholipid antibodies in normals and SLE patients is reviewed. The frequency of complications of antiphospholipid antibodies (thrombosis, pregnancy morbidity) in the literature and in the Hopkins Lupus Cohort is summarized.     

Unusual manifestations of the antiphospholipid syndrome

The classical clinical picture of the antiphospholipid syndrome (APS) is characterized by venous and arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or antibodies to the protein "cofactor" b2 glycoprotein I. Single vessel involvement or multiple vascular occlusions may give rise to a wide variety of presentations. Any combination of vascular occlusive events may occur in the same individual and the time interval between them also varies considerably from weeks to months or even years. Deep vein thrombosis, sometimes accompanied by pulmonary embolism, is the most frequently reported manifestation in this syndrome. Cerebrovascular accidents-either stroke or transient ischemic attacks-are the most common arterial thrombotic manifestations. Early and late fetal losses, premature births and pre-eclampsia are the most frequent fetal and obstetric manifestations. Additionally, several other clinical features are relatively common in these patients, i.e., thrombocytopenia, livedo reticularis, heart valve lesions, hemolytic anemia, epilepsy, myocardial infarction, leg ulcers, and amaurosis fugax. However, a large variety of other clinical manifestations have been less frequently described in patients with the APS, with prevalences lower than 5%. These include, among others, large peripheral or aortic artery occlusions, Sneddon's syndrome, chorea, transverse myelopathy, intracardiac thrombus, adult respiratory distress syndrome, renal thrombotic microangiopathy, Addison's syndrome, Budd-Chiari syndrome, nodular regenerative hyperplasia of the liver, avascular necrosis of the bone, cutaneous necrosis or subungual splinter hemorrhages. In this article, some of these "unusual" manifestations are reviewed.     

Management of antiphospholipid syndrome

Antiphospholipid syndrome (APS) is characterised by vascular thrombosis and/or obstetric morbidity in the presence of persistently positive antiphospholipid antibodies (aPL). Balancing an individuals' risk of thrombosis against the benefits and risks of antithrombotic therapies is crucial for optimising management and preventing morbidity in APS and asymptomatic aPL. Limitations in research studies have led to debate regarding best-practice. This review of the available literature makes the following recommendations. Those with asymptomatic aPL should only be treated with aspirin if they have persistently positive aPL, obstetric APS, or co-existent systemic lupus erythematosus. For those with APS, lower risk patients (i.e. first venous thrombosis) should be treated with warfarin to an INR 2.0–3.0. Those at higher risk (i.e. arterial thrombosis or recurrent events) should be treated with warfarin to an INR of >3.0. During pregnancy in APS, low molecular weight heparin (LMWH) and aspirin should be used and women should be under the care of obstetricians and physicians specialising in APS. Additional vascular and thrombotic risk factors should be actively reduced in all patient groups. Further randomised controlled trials are required, which should involve larger patient groups with APS diagnosed according to accepted criteria. This may mean that international and multi-centre trials are needed to ascertain the best treatment regimens.     

The diagnosis of the antiphospholipid syndrome

The concurrence of antiphospholipid (aPL) antibodies and thrombosis or pregnancy loss defines the 'antiphospholipid syndrome' (APS). The Sydney update of the classification criteria for definite APS diagnosis introduced numerous ameliorations to the previous preliminary consensus statement. Clinical criteria are now better defined as vascular thrombosis must be diagnosed on the basis of objective criteria. Moreover,additional risk factors for thrombosis or pregnancy loss must be taken into account before the diagnosis is made and should be described in detail in scientific reports. As far as laboratory criteria are concerned,the lack of standardization and the misinterpretation of results remain major problems often leading to overdiagnosis. A single positive test result out of the possible assays determining aPL antibodies (Lupus Anticoagulant, LAC, anticardiolipin, aCL and anti. beta2-Glycoprotein I, beta2-GPI, antibodies) is still sufficient,according to the Sydney criteria, to justify a diagnosis of APS. Nevertheless single test positivity may result in overdiagnosis or identification of low risk patients and use of all three tests seems more reasonable. Multiple positivity or (better) triple positivity in our experience allows for the identification of high risk patients for possible recurrence. In the near future, coagulation tests discriminating between a beta2-GPI and anti-prothrombin LAC may be useful in identifying high risk patients.     

Atherosclerosis and antiphospholipid syndrome

Atherosclerosis is an autoimmune/inflammatory disease associated with infectious, inflammatory, and autoimmune factors. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions. Heat-shock protein (hsp), oxidized low-density lipoprotein (LDL), and β2-GPI have been reported to elicit humoral and cellular immune response in both experimental animals and humans. These autoantigens are expressed within atherosclerotic lesions. Immunization with the given autoantigens elicits an immune response that influences lesion progression. Atherosclerosis susceptibility can be transferred by autoantigen-sensitized lymphocytes from immunized animals. Patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have a high risk for atherosclerotic cardiovascular events. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS. Immunological alterations, such as antibodies to oxidized LDL, antiphospholipid antibodies (aPL), antibodies to β-2 Glycoprotein (anti-β2-GPL), anti-prothrombin antibodies, may play a role in premature atherosclerosis in SLE and APS. Paraoxonase (PON1) is an enzyme with antioxidant activity attached to the circulating high-density lipoprotein (HDL) in plasma. Its function is to prevent oxidation of LDL, thereby accounting for the antioxidant properties and the atherosclerotic protective effects of HDL. The relationship between PON1 and aPL has been recently suggested. IgG anti-HDL and IgG anti-β2-GPI antibodies were associated with reduced PON1 activity in patients with SLE and primary APS. The determination of classic and new factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis in SLE and PAPS. Therapeutic strategies, including early control of disease and other risk factors, are essential to reduce morbidity and mortality.