Genomics and targeting antithrombotic therapy in antiphospholipid syndrome
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《血液学杂志》
A truly novel approach to the identification of subjects with antiphospholipid antibodies who are at high risk of thrombosis is reported using gene expression profiles.
In antiphospholipid syndrome, thrombosis is the principal clinical manifestation. It may occur in the arterial, the venous, or the microvascular compartments. The risk of recurrent thrombosis appears to be high and the consequences are often disabling and may be lethal. At present the mainstay of therapy is anticoagulation with coumarin, which is often continued long-term. Unfortunately, coumarin therapy is associated with substantial morbidity and mortality from iatrogenic hemorrhage.
The defining serologic marker for antiphospholipid syndrome is the presence and persistence of antiphospholipid antibody, typically lupus anticoagulant and/or anticardiolipin antibody. However, these antibodies may also be detectable in individuals who have no overt clinical manifestation of the syndrome. Currently, there is no reliable way to predict the likelihood of thrombosis in such subjects in order to target effective antithrombotic prophylaxis.
At present, risk stratification is poorly informed, based in part on observational data that relate antiphospholipid antibody characteristics to clinical events.1 These data suggest that lupus anticoagulant is more strongly associated with thrombosis than anticardiolipin antibody, and that the titer of anticardiolipin antibody is relevant, higher titers being of more importance. In addition, combinations of positive tests, including those for lupus anticoagulant, anticardiolipin, and anti-2GP1, appear to be of prognostic relevance.2 Consideration of this type of information, alongside an assessment of the clinical history and any additional risk factors for thrombosis, represents current best practice in management.
In the clinic an accurate measure of thrombosis risk in an individual subject with antiphospholipid antibody is required. In this issue of Blood, Potti and colleagues report on a novel approach that appears to show promise. They used RNA from peripheral blood mononuclear cells for DNA microarray analysis. In a carefully conducted study, they identified gene expression profiles that differentiated between subjects with antiphospholipid syndrome and those with a matching thrombosis history but no antiphospholipid antibodies. More surprisingly, and of potential clinical utility, expression profiles appeared to differentiate between subjects with antiphospholipid syndrome and those with antiphospholipid antibodies but no clinical event. However, some aspects of the study indicate the need for caution in interpreting the significance of these novel observations. First, no attempt was made to study subfractions of the starting mononuclear cell population, which also included platelets. Second, many of the apparently discriminatory genes have no known link to thrombosis. Third, the set of genes that discriminated subjects with thrombosis and antiphospholipid antibodies from those with thrombosis and no antibodies differed from the set that was informative in the comparison between subjects with antiphospholipid syndrome and those who had antiphospholipid antibodies but no thrombosis. Therefore, the possibility arises that some of the differences could be secondary to previous thrombosis.
There is a clinical need for improved prognostic measures in antiphospholipid syndrome. If the intriguing results obtained by Potti et al are confirmed, there is an indication to perform prospective studies using the same approach in asymptomatic subjects with antiphospholipid antibodies.
References
Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101: 1827-1832.
Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost. 2005;93: 1147-1152.(Michael Greaves)
In antiphospholipid syndrome, thrombosis is the principal clinical manifestation. It may occur in the arterial, the venous, or the microvascular compartments. The risk of recurrent thrombosis appears to be high and the consequences are often disabling and may be lethal. At present the mainstay of therapy is anticoagulation with coumarin, which is often continued long-term. Unfortunately, coumarin therapy is associated with substantial morbidity and mortality from iatrogenic hemorrhage.
The defining serologic marker for antiphospholipid syndrome is the presence and persistence of antiphospholipid antibody, typically lupus anticoagulant and/or anticardiolipin antibody. However, these antibodies may also be detectable in individuals who have no overt clinical manifestation of the syndrome. Currently, there is no reliable way to predict the likelihood of thrombosis in such subjects in order to target effective antithrombotic prophylaxis.
At present, risk stratification is poorly informed, based in part on observational data that relate antiphospholipid antibody characteristics to clinical events.1 These data suggest that lupus anticoagulant is more strongly associated with thrombosis than anticardiolipin antibody, and that the titer of anticardiolipin antibody is relevant, higher titers being of more importance. In addition, combinations of positive tests, including those for lupus anticoagulant, anticardiolipin, and anti-2GP1, appear to be of prognostic relevance.2 Consideration of this type of information, alongside an assessment of the clinical history and any additional risk factors for thrombosis, represents current best practice in management.
In the clinic an accurate measure of thrombosis risk in an individual subject with antiphospholipid antibody is required. In this issue of Blood, Potti and colleagues report on a novel approach that appears to show promise. They used RNA from peripheral blood mononuclear cells for DNA microarray analysis. In a carefully conducted study, they identified gene expression profiles that differentiated between subjects with antiphospholipid syndrome and those with a matching thrombosis history but no antiphospholipid antibodies. More surprisingly, and of potential clinical utility, expression profiles appeared to differentiate between subjects with antiphospholipid syndrome and those with antiphospholipid antibodies but no clinical event. However, some aspects of the study indicate the need for caution in interpreting the significance of these novel observations. First, no attempt was made to study subfractions of the starting mononuclear cell population, which also included platelets. Second, many of the apparently discriminatory genes have no known link to thrombosis. Third, the set of genes that discriminated subjects with thrombosis and antiphospholipid antibodies from those with thrombosis and no antibodies differed from the set that was informative in the comparison between subjects with antiphospholipid syndrome and those who had antiphospholipid antibodies but no thrombosis. Therefore, the possibility arises that some of the differences could be secondary to previous thrombosis.
There is a clinical need for improved prognostic measures in antiphospholipid syndrome. If the intriguing results obtained by Potti et al are confirmed, there is an indication to perform prospective studies using the same approach in asymptomatic subjects with antiphospholipid antibodies.
References
Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101: 1827-1832.
Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost. 2005;93: 1147-1152.(Michael Greaves)