The antiphospholipid syndrome

Antiphospholipid antibody syndrome (APS) is characterised by the presence of frequently recurring venous and/or arterial thrombosis, abortions and repeated evidence of lupus anticoagulants and/or anticardiolipin (aCL)-antibodies. The presence of lupus anticoagulants and/or high levels of aCL-antibodies in particular increases the risk of thrombosis. At present there are several models for the systemic and cell-damaging pathogenesis of phospholipid-antibodies. Where there are repeated occurrences of thrombo-embolic complications long-term anticoagulant treatment is indicated. For patients who have APS in pregnancy, the use of low-molecular heparin and acetylsalicylic acid (ASS) is recommended. According to recent research, a large number of antibodies can be found in APS patients, which are directed against phospholipids and plasmaproteins, but partly also against individual genetic polymorphism, which suggests focussing in future on the genetic basis of APS as well as on influencing "auto-immune thrombosis" by modulating the immune system.     

The antiphospholipid syndrome

Antiphospholipid syndrome is an autoimmune disorder characterized by the association between antiphospholipid antibodies and venous or arterial thrombosis or obstetric complications. In spite of the recent progresses, many aspects of this disease remain unclear. In this review, we briefly focus on the most important advances in the pathophysiology, diagnosis and treatment of this condition.     

The environment and antiphospholipid syndrome

The etiology of autoimmune diseases is multifactorial. The degree to which genetic and environmental factors influence susceptibility to autoimmune diseases is poorly defined. It is believed that versatile clinical presentations of autoimmune diseases stem from various combinations of the genetic and environmental factors. One of the newly diagnosed autoimmune diseases is the antiphospholipid syndrome (APS). APS is characterized by vascular thrombosis, and/or pregnancy morbidity associated with anticardiolipin (aCL), anti-beta2-glycoprotein-I (anti-beta2GPI) and lupus anticoagulant (LAC).     

The antiphospholipid syndrome and infection

Infectious agents have been implicated in the induction of antiphospholipid (aPL) antibodies and the development of the antiphospholipid syndrome (APS). This review focuses on the types of aPL antibodies detected in infections and addresses whether these antibodies are of clinical importance in patients with infections. Hepatitis C virus (HCV) infection is given special attention because this virus has the propensity to induce various autoimmune phenomena. Several aspects are emphasized that should be considered carefully when interpreting results. Most of the published data agree that thrombophilia is not observed in patients with infections (including HCV) because aPL antibodies are mostly the natural or nonpathogenic type. Thus, we do not recommend routinely testing for HCV in patients with APS. However, not all infection-associated aPL antibodies are cofactor independent. For instance, infections are increasingly recognized as a major precipitating condition of the catastrophic variant of APS, perhaps via mechanisms of molecular mimicry. Therefore, it may be possible to prevent this devastating evolution if the infectious process is promptly recognized and exhaustively treated.     

Pediatric antiphospholipid antibodies and antiphospholipid syndrome

Antiphospholipid syndrome (APS) can occur in children, like adults, with the same diverse spectrum of thrombotic sites but predominately with deep vein thrombosis and stroke. In contrast with adults, however, transient nonthrombogenic antiphospholipid (aPL) antibodies are seen more commonly, usually after childhood infections. In those with "true" aPL antibodies, recurrent thrombotic events seem less frequent than in adults, perhaps reflecting the less prothrombotic hemostatic state of childhood. Children with thrombotic events in APS present difficult management problems, as there is little evidence-based medicine. The duration and intensity of anticoagulation are unresolved management issues, but a target international normalized ratio of 2 to 3 is used by most. Multicenter randomized controlled trials would provide answers to some of these issues but are difficult to organize due to ethical issues and the rarity of the condition. A pediatric APS registry such as the Ped-APS Register is more easy to organize and can yield informative data.     

The molecular basis of antiphospholipid syndrome

We herein review evidence that the phospholipid-binding protein beta2 glycoprotein-1 (beta2GPI) is a causative autoantigen in APS. Recent work suggests that the molecular regions in beta2GPI that facilitate autoimmunization are those that promote binding to negatively charged phospholipids by means of strong positive (anionic) charge and hydrophobicity. Although many common infections can cause antiphospholipid antibodies to be produced in humans, such postinfectious aPL are rarely associated with thromboses or pregnancy morbidity, the central features of antiphospholipid syndrome (APS). We propose that the causes of APS include those infectious agents that mimic the above molecular domains in beta2GPI. In people who are susceptible to APS, tolerance to self-beta2GPI and phospholipids is likely to be broken by foreign bacterial or viral proteins that contain such beta2GPI-like epitopes.     

The lung in the antiphospholipid syndrome

Patients with antiphospholipid syndrome (APS) may develop a broad spectrum of pulmonary disease. Pulmonary thromboembolism and pulmonary hypertension are the most common complications, but microvascular pulmonary thrombosis, pulmonary capillaritis, and alveolar haemorrhage have also been reported. Clinicians should seriously consider these types of vascular injury when evaluating patients with APS who present with dyspnoea, fever, and infiltrates on chest radiography.     

Catastrophic antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a thrombotic disorder associated with autoantibodies that target membrane phospholipids and phospholipid-binding proteins, which regulate coagulation. APS is usually characterized by major arterial or venous occlusions, pregnancy complications, or both. In 1992, Asherson described an unusual variant of APS termed the catastrophic antiphospholipid syndrome (also known as Asherson's syndrome), the hallmark of which is rapid multiorgan failure caused by widespread small-vessel thrombi. Empiric treatments have improved the prognosis of patients, but half still die from thrombotic diathesis, even though those who survive the acute stages frequently remain well. Given the persistently high mortality rate, efforts have been underway to facilitate early diagnosis, institute effective treatments in a timely manner and to better understand the cause (or causes) of this extreme condition in order to improve outcomes.     

Catastrophic antiphospholipid syndrome

Catastrophic antiphospholipid syndrome, defined and documented in 1992, is a potentially fatal complication seen in patients with antiphospholipid antibody. It may arise de novo in patients not previously suspected as having an antiphospholipid syndrome, or it may complicate the course of patients currently treated for this syndrome. Precipitating or “trigger” factors have been identified in 55% of patients; the most common of these factors is infection. The precipitating factors should be avoided or energetically treated in patients with the antiphospholipid syndrome in order to prevent this “catastrophic” course. The clinical manifestations are those of multiorgan failure, and unusual vessels or organs can be involved. Treatment of the condition, with emphasis on effective anticoagulation, intravenous steroids, intravenous immunoglobulin, or plasma exchange, should be aggressive to achieve a satisfactory outcome. Regrettably, despite all available therapeutic options at this time, the mortality is still high (greater than 50%).     

Systemic antiphospholipid syndrome

The antiphospholipid syndrome (APS) was reported in the early 1980s as a triad of manifestations. Since than it became one of the most systemic conditions. Almost any organ and tissue may be involved in the disease, including the brain, the heart, the placenta, the endocrine system, the blood, the kidneys and many more. In the article it is suggested to add to the syndrome the word systemic in analogy to its sister condition, systemic lupus erythematosus.     

Neonatal antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a clinical entity characterized by arterial and venous thrombosis, adverse obstetric outcome and the presence of antibodies against phospholipids in serum or plasma. The objective of the present study is to describe a rare case of APS that occurred in a neonate born from a patient previously diagnosed as primary APS. A male, preterm born twin infant, whose mother had been diagnosed as primary APS, developed thrombocytopenia, livedo reticularis, pericardial effusion and thrombosis of the left subclavian and external jugular veins concomitantly with severe respiratory tract infection soon after his delivery, that culminated with his death two months after the birth, in spite of the large spectrum antibiotic therapy and all supportive measures. Laboratory findings included high titers of IgM anticardiolipin antibodies and moderate titers of IgG isotype and negative antinuclear antibody, configuring a case of neonatal APS. Neonatal APS is a rare clinical condition, with only a few cases described in the literature. Its occurrence may depend on the passage of antibodies through the placenta or, as it seems to have occurred in the present case, by the production of de novo antibodies by the fetus. The present case illustrates the necessity of a higher surveillance of the neonates born from mothers with primary APS or systemic lupus erythematosus (SLE) for the eventual development of such complication.     

Catastrophic antiphospholipid syndrome

Catastrophic APS is a potentially life-threatening condition with a high mortality, which requires high clinical awareness. New mechanisms for its production can only be explored if samples are obtained, stored, and dis-patched to investigation sites in Europe (Barcelona), the United States (Atlanta), and Japan (Sapporo). Details will be posted and made available on the International Registry Web Site in 2006. It is essential that the condition be diagnosed early and treated aggressively. The combination of high doses of iv heparin, iv steroids plus repeated doses of iv gammaglobulins or plasma exchange is the treatment of choice in patients with this severe condition. Additionally, preventive measures in patients with APS may be effective if the development of the catastrophic APS is to be avoided.     

Pediatric antiphospholipid syndrome

APS is rare in the pediatric age, but it represents an interesting phenomenon because most of the known "second hit" risk factors such as atherosclerosis, smoking, hypertension, contraceptive hormonal treatment, and pregnancy are not present in childhood. This could also be the reason for the prevalence of some clinical manifestations rather than others in PAPS.On the other hand, the increased frequency of infectious processes in the childhood age is likely responsible for the relatively high prevalence of non-pathogenic and transient aPL. Such points raise the problem of a different diagnosis or monitoring approach in pediatric APS. Of particular interest is the special entity of neonatal APS, which represents an in vivo model of acquired autoimmune disease, in which transplacentally acquired aPL cause thrombosis in the newborn. International registries for pediatric and neonatal APS are currently in place; epidemiologic, clinical, and laboratory re-search will help to shed light on all the still obscure aspects of this fascinating but rare disorder in the very young. Finally, treatment is less aggressive overall in pediatric APS, given the reluctance to anticoagulate children over the long term. Studies on the outcome of pediatric APS and the relative risks of prolonged anticoagulation in children are necessary to determine the type and duration of anticoagulation therapy.