Antiphospholipid Syndrome, Familial
Description
The designation 'antiphospholipid syndrome' was proposed for the association of arterial and venous thrombosis, recurrent fetal loss, and immune thrombocytopenia with a spectrum of autoantibodies directed against cellular phospholipid components. Anticardiolipin antibodies may react with cardiolipin and with other negatively charged phospholipids, including beta-2-glycoprotein I (B2GPI, APOH; 138700). The term 'lupus anticoagulant' refers to a heterogeneous group of antibodies, most commonly of the IgG type, that are detected by their inhibitory effect on coagulant-active phospholipid components of in vitro coagulation tests (summary by Matthey et al., 1989).
Shoenfeld et al. (2008) noted that antiphospholipid syndrome is characterized by up to 30 different autoantibodies, including those against platelets, glycoproteins, coagulation factors, lamins, mitochondrial antigens, and cell surface markers. Some of these may have an additive effect on the prothrombotic tendency of the syndrome.
Ruiz-Irastorza et al. (2010) reviewed pathophysiologic, clinical, diagnostic, and therapeutic advances related to the antiphospholipid syndrome.
Various autoimmune disorders that cluster in families, including autoimmune thrombocytopenia (188030), are discussed elsewhere (e.g., 109100, 269200).
Clinical FeaturesHellan et al. (1998) described a brother and sister with lupus anticoagulant, elevated anticardiolipin-immunoglobulin G levels, and systemic lupus erythematosus (SLE; 152700) or related autoimmune disorder. Both patients experienced venous thrombotic complications at an early age. The woman first presented with symptoms of spontaneous deep vein thrombosis of the right leg at the age of 22 years. The brother had been hospitalized at the age of 13 years for symptoms of arthritis of multiple joints and hepatosplenomegaly. He was found to have serologic and histologic evidence for lupus. At the age of 17 years, he presented with deep vein thrombosis of the right leg after a minor trauma. An association between the presence of lupus anticoagulant and the development of abnormalities of the heart valves was suggested by Hoshide et al. (1998), who described typical mitral stenosis in a patient with SLE associated with lupus anticoagulant.
Brenner et al. (1996) observed a 23-year-old female and her 19-year-old sister, the offspring of a first-cousin marriage, who presented with unusual recurrent severe thromboembolic phenomenon and were found to have familial antiphospholipid syndrome and also to be heterozygous for the R506Q mutation of factor V (612309.0001). The coexistence of hereditary and acquired APC-resistance was thought to explain the severity of the thromboembolism. The older sib presented with deep vein thrombosis of the proximal left leg and intrauterine fetal death at 20 weeks of gestation in her third pregnancy. During her fourth pregnancy she received enoxaparine from the tenth week of gestation, but intrauterine fetal death occurred at 20 weeks of gestation. Three weeks later she developed right popliteal deep vein thrombosis. The younger sister was admitted to hospital with infarction of lumbar vertebra L4 demonstrated by bone scan, first-trimester abortion, and pancytopenia.
Akiguchi et al. (1999) reported a 2-generation family with 3 generations of cousin marriages that was segregating lupus anticoagulant and Binswanger disease. The 60-year-old proband began insidious decline at age 57. Lupus anticoagulant was positive but anticardiolipin antibodies were negative. Multiple lacunes were present in a younger brother, in a younger sister, who also had venous thrombosis, and in 1 daughter, who also had SLE.
Gelfand et al. (1999) reported the systemic and ophthalmic involvement in 39 consecutive patients with primary antiphospholipid syndrome. The first 20 consecutive patients underwent retinal fluorescein angiography. The most common forms of systemic involvement included fetal loss (46%), central nervous system involvement (44%), and venous thrombosis (41%). Thirty-three percent of patients had ocular symptoms; these were usually visual disturbances and were most often transient. Pathologic ocular findings directly related to the disease were found in 13% of the patients, and only 5% had intraocular pathology, which consisted of very mild retinopathy. Ocular findings were present in only 6% of the asymptomatic patients. Routine retinal angiography did not reveal any additional information. The authors concluded that ocular involvement in the primary antiphospholipid syndrome is uncommon. Transient visual disturbances are common, although most of them are related to central nervous system rather than ocular ischemia.
Miserocchi et al. (2001) evaluated the ophthalmic features in 13 patients presenting with ocular inflammation in the presence of anticardiolipin antibodies. All patients had abnormal titers of anticardiolipin antibodies, predominantly the IgG isotype; 46% had markers of immune activation. Systemic symptoms were frequently present in association with ocular disease. The most common ocular symptom at presentation was blurred vision (62%), followed by pain (23%) and visual loss (15%). Seventy-six percent of patients had anterior segment abnormalities, including iritis (62%), scleritis (15%), and filamentary keratitis (7%). The most common posterior segment feature was retinal vasculitis (60%), followed by vitritis (38%), retinal detachment (15%), scleritis (7%), and central retinal artery occlusion (7%).
MappingHudson et al. (1997) found a possible linkage between the HLA-DRB1*14 allele on chromosome 6p21.3 and familial antiphospholipid syndrome.
InheritanceFamilial occurrence of lupus anticoagulant was reported by Exner et al. (1980) and Mackie et al. (1987). In these reports, the index cases had systemic lupus erythematosus or related immune disorders, while many of their family members had a variety of clinical serologic features suggestive of a lupus-like syndrome. Matthey et al. (1989) described a family in which several members had anticardiolipin antibodies and 2 had lupus anticoagulant, but all were asymptomatic.
To develop diagnostic criteria for a familial form of antiphospholipid syndrome, Goel et al. (1999) studied families with more than one affected member, examined possible modes of inheritance, and determined linkage to potential candidate genes. In 7 families, 30 of 101 family members met diagnostic criteria for the syndrome. Segregation studies rejected both environmental and autosomal recessive models, and the data were fitted best by either a dominant or codominant model. Linkage analysis showed independent segregation of antiphospholipid syndrome and several candidate genes.
PathogenesisMcNeil et al. (1990) identified beta-2-glycoprotein I (B2GPI, APOH; 138700) as a cofactor required for antiphospholipid antibodies (APA) to bind to cardiolipin. These findings suggested that APA are directed against a complex antigen that includes B2GPI. In addition, B2GPI bound to anionic phospholipids in the absence of anticardiolipin antibodies. McNeil et al. (1990) hypothesized that anticardiolipin APA may interfere with the function of apoH in vivo, which may explain the association of these antibodies with thrombotic tendencies.
Molecular GeneticsHirose et al. (1999) found that a polymorphism in the APOH gene (V247L) was significantly associated with decreased levels of anti-beta-2-glycoprotein I (B2GPI) antibodies in Asian patients with antiphospholipid syndrome in a study of 370 healthy controls from different racial backgrounds and 149 patients with APS. The V allele and the VV genotype were found more frequently among Asian patients with antiphospholipid syndrome than among controls (p = 0.0028 and p = 0.0023, respectively). There were no significant differences in allele or genotype frequencies when comparing Caucasian or African American APS patients with appropriate controls. The differences in allele and genotype frequencies seen in Asian APS patients were restricted to those with anti-B2GPI antibodies.
Animal ModelIn a mouse model of antiphospholipid syndrome induced by passive transfer of human antiphospholipid antibodies, Girardi et al. (2003) showed that complement activation plays an essential and causative role in fetal loss and tissue injury. Specifically, they identified the proinflammatory sequelae of the interaction of C5a and C5a receptor (C5R1; 113995) and the recruitment of neutrophils as the critical intermediates linking pathogenic antiphospholipid antibodies to fetal damage. Their conclusions were based on the fetal protective effects of C5a receptor deficiency and C5a receptor antagonist peptide, the similar findings with anti-C5 mouse antibody and in C5 -/- mice, where C5a generation is prevented, and the effects of neutrophil depletion.