Management of the Antiphospholipid Syndrome: New Approaches
Alan M Seif; Yong Hwang; Silvia S Pierangeli
Abstract and Introduction
Abstract
The antiphospholipid syndrome (APS) is an autoimmune, multisystemic disorder associated with recurrent thrombosis (arterial and/or venous) and pregnancy loss, among other clinical manifestations. The hallmark of the disease is the presence of antiphospholipid (aPL) antibodies (i.e., anticardiolipin [aCL] antibodies, lupus anticoagulant and anti-â2glycoprotein I (anti-â2GPI) antibodies). This review addresses current modalities used for primary prevention and treatment of clinical manifestations in patients with APS. Furthermore, based on new knowledge regarding the pathogenic and molecular mechanisms that are triggered and mediated by aPL antibodies, new targeted modalities for treatment in APS are discussed. These new treatments potentially more effective and with fewer side effects might be used in the future to treat clinical manifestations of this disease that are associated with devastating consequences, and are pending adequate clinical trials.
Introduction
Antiphospholipid syndrome (APS) is an autoimmune and multisystem disorder of thrombosis and pregnancy loss, associated with the persistent presence of antiphospholipid (aPL) antibodies. These antibodies are directed against protein antigens that bind to anionic phospholipids, such as â2glycoprotein I (â2GPI) and prothrombin. Thrombosis is the major manifestation in patients with APS, but the spectrum of symptoms and signs associated with aPL antibodies has considerably broadened, and other manifestations such as thrombocytopenia, nonthrombotic neurological syndromes, livedo reticularis, skin ulcers, hemolytic anemia, pulmonary hypertension, cardiac valve abnormality and atherosclerosis have also been related to the presence of these antibodies.
Antiphospholipid syndrome was first coined more than 25 years ago, and has often been referred to as 'the syndrome of the black swan', given its unusual presentation.[1] APS was first described in a subset of patients with systemic lupus erythematosus (SLE) that had abnormal lupus anticoagulant (LAC) test results. APS can occur in the presence of other autoimmune disorders, particularlySLE, or in the absence of SLE or other autoimmune disorders (primary APS). APS is now recognized as the most common cause of acquired hypercoagulability in the general population,[4] and as the most important treatable cause of recurrent miscarriage. aPL antibodies can be detected in up to 40% of SLE patients and affect disease morbidity since they are associated with recurrent thrombosis, pregnancy loss, thrombocytopenia, and worse lupus nephritis and kidney transplantation outcomes.
Cardiovascular morbidity and mortality is a frequent complication in SLE, where the risk of myocardial infarction is raised 50-fold. In addition to traditional risk factors such as hypertension or diabetes, several factors more specifically related to lupus are proposed to be of importance, including inflammation and aPL antibodies. A study of patients with SLE demonstrated that anticardiolipin (aCL) positivity preceded the onset of a more severe form of SLE, as well as SLE complicated with thrombosis, pregnancy loss and thrombocytopenia.
The preliminary classification criteria for APS were revised in 2006, and include the presence of both clinical and laboratory criteria. Patients must have vascular thrombosis (arterial or venous) and/or pregnancy morbidity. With respect to vascular thrombosis, any tissue or organ must be confirmed with imaging or histopathology, for which histology excludes inflammation in the vessel wall. Regarding pregnancy morbidity, one of the following must be present:
Abstract
The antiphospholipid syndrome (APS) is an autoimmune, multisystemic disorder associated with recurrent thrombosis (arterial and/or venous) and pregnancy loss, among other clinical manifestations. The hallmark of the disease is the presence of antiphospholipid (aPL) antibodies (i.e., anticardiolipin [aCL] antibodies, lupus anticoagulant and anti-â2glycoprotein I (anti-â2GPI) antibodies). This review addresses current modalities used for primary prevention and treatment of clinical manifestations in patients with APS. Furthermore, based on new knowledge regarding the pathogenic and molecular mechanisms that are triggered and mediated by aPL antibodies, new targeted modalities for treatment in APS are discussed. These new treatments potentially more effective and with fewer side effects might be used in the future to treat clinical manifestations of this disease that are associated with devastating consequences, and are pending adequate clinical trials.
Introduction
Antiphospholipid syndrome (APS) is an autoimmune and multisystem disorder of thrombosis and pregnancy loss, associated with the persistent presence of antiphospholipid (aPL) antibodies. These antibodies are directed against protein antigens that bind to anionic phospholipids, such as â2glycoprotein I (â2GPI) and prothrombin. Thrombosis is the major manifestation in patients with APS, but the spectrum of symptoms and signs associated with aPL antibodies has considerably broadened, and other manifestations such as thrombocytopenia, nonthrombotic neurological syndromes, livedo reticularis, skin ulcers, hemolytic anemia, pulmonary hypertension, cardiac valve abnormality and atherosclerosis have also been related to the presence of these antibodies.
Antiphospholipid syndrome was first coined more than 25 years ago, and has often been referred to as 'the syndrome of the black swan', given its unusual presentation.[1] APS was first described in a subset of patients with systemic lupus erythematosus (SLE) that had abnormal lupus anticoagulant (LAC) test results. APS can occur in the presence of other autoimmune disorders, particularlySLE, or in the absence of SLE or other autoimmune disorders (primary APS). APS is now recognized as the most common cause of acquired hypercoagulability in the general population,[4] and as the most important treatable cause of recurrent miscarriage. aPL antibodies can be detected in up to 40% of SLE patients and affect disease morbidity since they are associated with recurrent thrombosis, pregnancy loss, thrombocytopenia, and worse lupus nephritis and kidney transplantation outcomes.
Cardiovascular morbidity and mortality is a frequent complication in SLE, where the risk of myocardial infarction is raised 50-fold. In addition to traditional risk factors such as hypertension or diabetes, several factors more specifically related to lupus are proposed to be of importance, including inflammation and aPL antibodies. A study of patients with SLE demonstrated that anticardiolipin (aCL) positivity preceded the onset of a more severe form of SLE, as well as SLE complicated with thrombosis, pregnancy loss and thrombocytopenia.
The preliminary classification criteria for APS were revised in 2006, and include the presence of both clinical and laboratory criteria. Patients must have vascular thrombosis (arterial or venous) and/or pregnancy morbidity. With respect to vascular thrombosis, any tissue or organ must be confirmed with imaging or histopathology, for which histology excludes inflammation in the vessel wall. Regarding pregnancy morbidity, one of the following must be present:
- One or more unexplained death of a normal fetus at or beyond the 10th week of gestation;
- One or more premature birth of a normal neonate at or beyond the 34th week of gestation due to severe pre-eclampsia, eclampsia or placental insufficiency;
- Three or more unexplained, consecutive, spontaneous abortions before the 10th week of gestation that excludes maternal, anatomic, hormonal or parental chromosomal anomalies.
Laboratory criteria include the presence of either LAC in plasma of medium to high titer IgG or IgM aCL isotypes, and or IgG or IgM anti-â2GPI, on two or more occasions, at least 12 weeks apart.
Antiphospholipid syndrome can be described as a spectrum of multiorgan involvement. At one end, healthy individual and elderly patients may develop aPL antibodies in the absence of clinical manifestations, and this is called asymptomatic APS. This may be due to an infection, malignancy, may be drug induced, or a result of the aging process, and the titers of aPL antibodies are usually low. On the other end, catastrophic APS (CAPS) comprises 1% of APS cases and is associated with multiple, widespread vascular occlusions, high titer aPL antibody and significant mortality.
The majority of patients present somewhere inbetween, with either primary or secondary APS. Antiphospholipid antibodies are heterogeneous and bind to various protein targets, including the plasma protein â2GPI, prothrombin, tissue plasminogen activator, plasmin, annexin A2 and thrombin.[1620] There are many mechanisms involved in APS, and many in vivo animal model studies have described the pathogenesis of thrombosis, endothelial cells and pregnancy loss. Investigators have demonstrated that endothelial cells express significantly higher amounts of cellular adhesion molecules (CAMs), such as ICAM-1, VCAM-1 and E-selectin, when incubated with aPL antibodies in vitro. Our group has demonstrated that aPL antibodies activated endothelium in vitro and in mouse models, and this correlated with the enhancement of thrombus formation in vivo.
However, there have been limitations, and our understanding of the pathophysiology of APS is incomplete owing to unknown mechanisms of thrombosis or to heterogeneity of the aPL antibodies. In this article, we will first review the role of current therapies, along with concomitant side effects, and with what is currently known on the pathophysiology of this rare but serious condition. Importantly, we discuss possible new targeted treatments to ameliorate APS-related clinical manifestations.
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Antiphospholipid syndrome can be described as a spectrum of multiorgan involvement. At one end, healthy individual and elderly patients may develop aPL antibodies in the absence of clinical manifestations, and this is called asymptomatic APS. This may be due to an infection, malignancy, may be drug induced, or a result of the aging process, and the titers of aPL antibodies are usually low. On the other end, catastrophic APS (CAPS) comprises 1% of APS cases and is associated with multiple, widespread vascular occlusions, high titer aPL antibody and significant mortality.
The majority of patients present somewhere inbetween, with either primary or secondary APS. Antiphospholipid antibodies are heterogeneous and bind to various protein targets, including the plasma protein â2GPI, prothrombin, tissue plasminogen activator, plasmin, annexin A2 and thrombin.[1620] There are many mechanisms involved in APS, and many in vivo animal model studies have described the pathogenesis of thrombosis, endothelial cells and pregnancy loss. Investigators have demonstrated that endothelial cells express significantly higher amounts of cellular adhesion molecules (CAMs), such as ICAM-1, VCAM-1 and E-selectin, when incubated with aPL antibodies in vitro. Our group has demonstrated that aPL antibodies activated endothelium in vitro and in mouse models, and this correlated with the enhancement of thrombus formation in vivo.
However, there have been limitations, and our understanding of the pathophysiology of APS is incomplete owing to unknown mechanisms of thrombosis or to heterogeneity of the aPL antibodies. In this article, we will first review the role of current therapies, along with concomitant side effects, and with what is currently known on the pathophysiology of this rare but serious condition. Importantly, we discuss possible new targeted treatments to ameliorate APS-related clinical manifestations.
DOWNLOAD COMPLETE PDF HERE
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