Coagulation and fibrinolytic activities in 2 siblings with β2-glycoprotein I deficiency

Takeuchi, Rie; Atsumi, Tatsuya; Ieko, Masahiro; Takeya, Hiroyuki; Yasuda, Shinsuke; Ichikawa, Kenji; Tsutsumi, Akito; Suzuki, Koji; Koike, Takao

doi:10.1182/blood.v96.4.1594.h8001594_1594_1595

Cited by 6 publications

(6 citation statements)

References 12 publications

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“…To prevent the β2GPI/antibody complexes from the binding to receptors, we designed an inhibitor that a) targets β2GPI and b) binds tightly to β2GPI/antibody complexes expressing the dimeric β2GPI but binds weakly to β2GPI monomers. These requirements have the following rationale: First, complete β2GPI deficiency in humans, although rare, does not lead to apparent health problems [35] , [36] , [37] , therefore the inhibitor that targets β2GPI will not disrupt normal biological processes. Second, β2GPI/anti-β2GPI antibody complexes expressing dimeric β2GPI but not monomeric β2GPI are pathologically important [28] , [38] , therefore the inhibitor should bind preferentially to β2GPI/anti-β2GPI complex compared to β2GPI monomers.…”

Section: Introductionmentioning

confidence: 99%

A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

et al. 2010

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Backgroundβ2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of β2GPI generated by anti-β2GPI antibodies is pathologically important, in contrast to monomeric β2GPI which is abundant in plasma.Principal FindingsWe created a dimeric inhibitor, A1-A1, to selectively target β2GPI in β2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of β2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of β2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of β2GPI present in human serum, β2GPI purified from human plasma and the individual domain V of β2GPI. We demonstrated that when β2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of β2GPI to cardiolipin, regardless of the source of β2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of β2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-β2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric β2GPI to cardiolipin.ConclusionsOur results suggest that the approach of using a dimeric inhibitor to block β2GPI in the pathological multivalent β2GPI/antibody complexes holds significant promise. The novel inhibitor A1-A1 may be a starting point in the development of an effective therapeutic for antiphospholipid syndrome.

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Section: Introductionmentioning

confidence: 99%

A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

et al. 2010

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“…The uncertainty regarding the physiological importance of ␤2GPI as a regulator of coagulation is reinforced by the observation that individuals with undetectable levels of ␤2GPI seem to suffer neither from clotting nor from bleeding complications. 31,32 Dysregulation of the coagulation pathway leading to thrombosis is thought to be a central event in the pathogenesis of several common diseases such as myocardial infarction and stroke. Such disorders are thought to be the result of a multifactorial process and it is unknown whether ␤2GPI has any role in the pathogenesis of these conditions.…”

Section: Paper Introductionmentioning

confidence: 99%

Circulating levels of β2-glycoprotein I in thrombotic disorders and in inflammation

Lin

Murphy

White

et al. 2006

Lupus

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Beta2-glycoprotein I (beta2GPI) is a plasma protein suspected to have a role in inhibition of thrombosis. This suspicion is reinforced by the observation that beta2GPI is the major target for autoantibodies in the antiphospholipid syndrome. However, little is known about its circulating levels in common thrombotic diseases or inflammation. We measured beta2GPI levels in 344 healthy controls, 58 normal pregnancies, 102 patients with non-haemorrhagic stroke, 121 patients with acute coronary syndrome and 200 patients with elevated C-reactive protein (CRP). In healthy individuals, we found a strong positive correlation between age and beta2GPI concentration (r = 0.274, P < 0.001) and that beta2GPI levels fall significantly after the eighth week of pregnancy (P = 0.002). We also found significantly reduced levels of beta2GPI in patients with stroke and in elderly patients with myocardial syndrome (P = 0.013 and 0.043). However, in neither group did beta2GPI levels change in the following six months, suggesting that the reduced levels were not a transient post-event phenomenon. In patients with inflammation, beta2GPI levels showed a significant negative correlation with CRP (r = -0.284, P < 0.001) and positively correlated with albumin and transferrin (r = 0.372 and 0.453, respectively with P < 0.001 for both). Furthermore, the largest reduction in beta2GPI levels occurred in patients with the highest CRP values (P < 0.001).

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“…Beyond the demonstration that b 2 GPI is the target of antibodies in the antiphospholipid syndrome (APS), its physiological function remains largely unknown. There have been publications that beta2-glycoprotein I deficient patients have a shortened dilute Russell's viper venom time but the exact mechanism is unknown (Takeuchi et al, 2000). One research group was able to breed beta2GPI null mice and did not find apparent haemostatic differences compared to wildtype mice.…”

Section: Discussionmentioning

confidence: 99%

Indications for a protective function of beta2‐glycoprotein I in thrombotic thrombocytopenic purpura

Hovinga

et al. 2012

Br J Haematol

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SummaryIt has been shown that b 2 -glycoprotein I (b 2 GPI) interacts with von Willebrand factor (VWF) in a glycoprotein (GP)Ib binding state. Given the presence of active VWF multimers in thrombotic thrombocytopenic purpura (TTP), we speculated that b 2 GPI might play a role in TTP. We found that b 2 GPI plasma levels were significantly lower in acute and remission TTP patients than in normal controls, showing a direct correlation with ADAMTS 13 levels and an inverse correlation with the extent of VWF activation. In vitro flow experiments demonstrated that b 2 GPI can block platelet adhesion to endothelial cell-derived VWF strings. We confirmed the direct binding of b 2 GPI to VWF by surface plasmon resonance, and determined that domain I of b 2 GPI is the binding site of VWF A1 domain. Adhesion of b 2 GPI to erythrocytes and platelets was increased in the presence of active VWF, indicating that b 2 GPI may be cleared from the circulation during TTP episodes together with blood cells. Our findings suggest that b 2 GPI may protect from the effects of hyper-functional VWF by inhibiting its interaction with platelets.

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Coagulation and fibrinolytic activities in 2 siblings with β2-glycoprotein I deficiency

Cited by 6 publications

References 12 publications

A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

Circulating levels of β2-glycoprotein I in thrombotic disorders and in inflammation

Indications for a protective function of beta2‐glycoprotein I in thrombotic thrombocytopenic purpura

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