Antiphospholipid Syndrome

Hughes’ Syndrome

Introduction

Antiphospholipid syndrome (APS) was first coined to denote the clinical correlation between antiphospholipid antibodies and a syndrome of episodes thrombosis in arteries/veins (Chi 2002). APS is an autoimmune disorder, in which the immune system produces antibodies against the body’s own phospholipids (a type of fat that contains phosphorous) or to their binding proteins (J.J. Mason et al. 2002). APS is closely related to systemic lupus in that both of these conditions involve an autoantibody response. The history of this disorder dates back to the 1950’s when an in vitro anticoagulant phenomenon was first described in patients with systemic lupus erythematosus (SLE). Later in 1963, a paradoxical thrombitic event was occurring in these patients. In 1972 the term lupus anticoagulant was coined to denote the in vitro phenomenon caused by an inhibitor directed against phospholipid in the clotting cascade. http://www.heartcenteronline.com/myheartdr/common/articles.cfm?ARTID=387. Antiphospholipid antibodies have also been detected in patients with myasthenia gravis and many other autoimmune diseases (Sato et al. 2002).

Symptoms

APS elevates the body’s risk to problems like blood clots, miscarriages, and low platelet counts (thrombocytopenia). The most common sign of antiphospholipid syndromes among women is a history of miscarriages and complications during labor. Because this syndrome affects the way blood clots and acts on phospholipids its pathology is seen in almost all organs in different manifestations. Two types of antiphospholipid antibodies have been described as part of the syndrome. One is the circulating lupus anticoagulant, and the other is an antibody to a specific phospholipid called cardiolipin. A presentation of the different manifestations of this condition presented below.

Table 1. Systemic manifestations of antiphospholipid syndrome. This table provides an inventory of the different problems that result from APS.

Rheumatology	SLE, discoid LE, subacute cutaneous LE, Sjogren's syndrome, RA, vasculitis, scleroderma, polymyosistis, dermatomyoisistis
Neurology	cerebral ischemia, stroke, migraine, epilepsy, chorea, myelopathy, multiple sclerosis
Cardiology	myocardial infarction, pulmonary hypertension, valvular disease
Nephrology	renal vein thrombosis, glomerular thrombosis, thrombotic microangiopathy, vasculitis, malignant hypertension
Endocrinology	Addison's disease from adrenal thrombosis
Gastroenterology	gut ischemia, hematemesis, liver vein thrombosis, Budd-Chiari syndrome
Dermatology	livedo reticularis, Sneddon's syndrome, skin ulcers, skin nodules
Hematology	thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia
Obstetrics	recurrent spontaneous abortion
Intensive care	thromboembolism, adult respiratory distress syndrome
Surgery	bone necrosis, postoperative thrombosis

http://www.uveitis.org/Enhanced/MD_info/antiphospholipid_syndrome.htm

Diagnosis

APS is usually diagnosed with the help of a complete medical history and physical examination that are consistent with the symptoms of APS. The definitive test for APS is a blood test that reveals the presence of autoantibodies. There are several different test that are usually administered in order to diagnose APS. One of these test is called the Lupus Anticoagulant (LA). The lupus anticoagulant is an immunoglobulin, either IgG or IgM that prolongs clotting time in vitro because they agglutinate phospholipids present in the plasma thereby prevent their participation as cofactors in coagulation steps. The apparent action appears to be the inhibition of the conversion of prothrombin to thrombin. These test are not a 100 percent and thus there criteria must be met in order for a positive lupus anticoagulant test: 1-extended partial thromboplatin time; 2- failure to correct test by mixing patient plasma with normal plasma; 3-normalization of test with phospholipids. Anticardiolipin (aCL) antibody is detected with an enzyme-linked assay (ELISA) that allows for the identification and quantification of specific isotypes. IgG is the major predictor of thrombosis and pregnancy lost while IgM is associated with hemolytic anemia. The higher-titer of IgG anticardiolipin antibody (>40GPL) correlates strongly with thrombosis and fetal loss. Thus most patients with APS have medium to high IgG anticardiolipin antibody levels. www.medstudents.com.br/reumat/reumat2.htm. Because the levels of IgG correlate so strongly with the symptoms of APS new test have been designed to monitor the level of this antibody better. Newer assays for this condition use phosphatidylserine, a mixture of negatively charged phospholipids or beta2-glycoproteins, have been shown to make more specific measurements of the amounts of antibodies present in APS (Chi 2002). Other studies suggest that IgG anti-phosphatidylserine-prothrombin complex antibodies should be included in diagnostic test for APS ( Kaburaki J et al. 2003).

Molecular Pathogenesis

Although the mechanism of action of antiphospholipid antibodies is unknown advances are being made in that regard. As stated earlier, the antibodies bind to the anionic phospholipids of platelets and prothrombin. Seemingly there exist a discrepancy between the prolongation of clotting time in vitro and thrombosis in vivo. There doesn’t seem to be a satisfactory explanation for this yet. In vitro lupus anticoagulant is believed to extend clotting time by binding phospholipids and thereby hindering the surface area necessary for the binding of the prothrombinase complex. But the mechanism associated with thrombosis in vivo is unknown which makes this condition very contradictory in nature because on one hand clotting time is extended but on the other hand this condition promotes uncontrollable localized clotting. Other postulations cite the up regulation of endothelial cell adhesion molecules as the origin of pathogenesis. Yet some hypotheses maintain that is the disruption of the membrane during lipid peroxidation, or a dysfunction of endogenous anticoagulants, or even abnormal platelet aggregation. Whether all causes APS, some, or none of these conditions there are treatments that provide relief from the symptoms (Manson J.J 2003). Studies have also cited circumstantial evidence that a protein called Beta2-Glycoprotein I (beta2-GPI) is involved in the molecular pathogenesis of APS. There is a plethora of circumstantial evidence that suggests Beta2-GPI is indeed the main antigen for Antiphospholipid (aPL) antibodies. (Matsuura E 2003). These studies have shown that Beta2-GPI bears an epitope for autoantibodies and that the binding of this protein affects the activation of factor XII, which is an initiator of intrinsic coagulation and involved in fibrinolytic systems. This partly explains why autoantibodies are associated with thrombosis in APS individuals (Takeuchi R 2002). Experiments have also determined that molecular mimicry can occur in experimental induction of APS like symptoms demonstrating that bacterial peptides homologous with beta2-GPI can elicit the pathogenic autoantibodies associated with APS (Blank 2002).

Figure 1. This figure is a pictorial representation of the binding of anti- beta2-Glycoprotein I antibodies. Beta2-GPI is a phospholipid binding protein and is believed to be the main antigenic molecule for aPL antibodies.

http://prl.humc.edu/obgyn/web/fellow/conferences/antiph.htm

Treatments

Because the cause of the condition is unclear the facilitation of preventative therapies has been slow to develop. However drugs like aspirin and other coagulants are taken to reduce the risk of blood clots, miscarriages, and low platelet counts. Also pregnant patients with APS are given additional sonograms to monitor the growth of the fetus. APS mothers during the first and second trimesters are also sometimes prescribed low does of aspirin in conjunction with twice-daily injections of an anticoagulant like heparin( www.womens-health.co.uk/antiphos.htm). “Cortisone-related medications, such as prednisone, have been used to suppress the immune activity and inflammation in patients with certain features of the condition. For patients with systemic lupus erythematosus who also have anticardiolipin syndrome, hydroxychloroquine (Plaquenil) has been reported to add some protection against blood clotting http://www.medicinenet.com/Antiphospholipid_Syndrome/page2.htm.” Because the exact nature of the condition and differences in the phenotype of the disease each person is treated differently. People are also given drugs like warfarin to combat thrombosis in vivo. Clinical trials are underway for at least one investigational drug for the treatment of antiphospholipid (anticardiolipin) antibodies. For more information on this subject visit Center Watch’s website for information on clinical trials concerning antiphospholipid syndrome. http://www.centerwatch.com/patient/studies/stu32314.html

Immunology Course Page

Biology Home Page

Antiphospholipid Antibody - definition & history - Thomas G. DeLoughery 1999

Return to top of Page

Davidson College

References:

Manson, J.J., Isenberg D.A. (2003). Antiphospholipid syndrome. The International Journal of Biochemistry & Cell Biology. 35(7):1015-1020.

Sato, Kaji M., Kunoh, H, Watanabae A, Aizawa H, Oizumi K, Abe. (2002) Antiphospholipid syndrome and multiple ischemic strokes in a patient with myasthenia gravis. Kurume Med J. 49(4)211-6.

Kaburaki J, Kuwana M, Ikeda Y (2003). Clinical signifigance of anti-phosphatidylserine-prothrombin complex antibodies in the diagnosis of anti-phospholipid syndrome. Rinsho Ketsueki. 44(1):28-30.

Matsura E, Kobayashia K, Koikeb T, Shoenfeld Y, Khamashta MA, Hughes Gr. 2003. Atherogenic autoantigen:oxidized LLDL complexes with beta 2-glycoproteins I. Immunobiology. 207 (1):17-22.

Takeuchi R, Atsumi T, Ieko M, Amasaki Y, Ichikawa K, Koike T. 2002. Suppressed intrinsic fibrinolytic activity by monoclonal anti-beta-2-glycoprotein I autoantibodies: possible mechanism for thrombosis in patients with antiphospholipid syndrome.

Blank Miri, Krause Ilan, Fridkin Mati et al. 2002. Bacterial induction of autoantibodies to B2-glycoportein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 109 (6) 797-804.

Gharavi AE, Pierangeli SS, Espinola RG, Liu X et al. 2002. Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide causes thrombosis and activation of endothelial cells in vivo. Arthritis Rheum. 46(2):545-52

McIntyre J A , Wagenknecht DR, Faulk WP. 2003 Antiphospholipid Antibodies: discovery, definitions, detection and disease. Prog Ipid Res. 42(3): 176-237.

Disclaimer: This web page was design as an assignment for an undergraduate course at Davidson College. This page is not intended to provide medical advice or instruction on treatment of APS. Please consult your physician.

This page was designed and is maintained by Alfred L. Bowie Jr. If you have any questions about this page you can contact me via email at frbowie@davidson.edu