The Putative Mechanism of Thrombosis in Antiphospholipid Syndrome: Impairment of the Protein C and the Fibrinolytic Systems by Monoclonal Anticardiolipin Antibodies

Ieko, Masahiro; Sawada, Kenichi; Koike, Takao; Notoya, Atsushi; Mukai, Masaya; Kohno, Michifumi; Wada, Norio; Itoh, Tomohiro; Yoshioka, Narihito

doi:10.1055/s-2007-994958

Cited by 35 publications

(19 citation statements)

References 17 publications

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“…Moreover, antiphospholipid antibodies were found in this patient as well as in other patients with thrombotic complications and/or purpura fulminans following varicella infection [3, 4, 10, 11]. It is possible that the simultaneous presence of a protein S deficiency and antiphospholipid antibodies concur to explain the severity of the clinical manifestation [4, 12]. Many children develop anti-protein-S antibodies following varicella, but in children with purpura fulminans following a chickenpox infection, significantly higher protein S antibody levels and lower protein S levels are found than in those without this complication [13].…”

Section: Discussionmentioning

confidence: 82%

Purpura fulminans in a Child as a Complication of Chickenpox Infection

Campanelli

Kaya²,

Ozsahin³

et al. 2004

Dermatology

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Purpura fulminans is a thrombotic disease that can occur during infections, disseminated intravascular coagulation or in the context of an acquired or congenital protein C or S deficiency. Here we report the case of a 4-year-old child who developed, 5 days after a chickenpox infection, large painful ecchymotic, necrotizing and retiform plaques on the lower extremities. Laboratory analyses revealed very low protein S levels as well as anticardiolipin antibodies. Aggressive treatment by low-molecular-weight heparin, steroids, intravenous immunoglobulins and fresh frozen plasma was able to prevent the extension of the lesions and to correct the coagulation abnormalities. No lesions required skin grafting. As in our patient, an acquired protein S deficiency is probably responsible for most cases of purpura fulminans occurring after varicella, but the concomitant presence of antiphospholipid antibodies may also play a role.

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Section: Discussionmentioning

confidence: 82%

Purpura fulminans in a Child as a Complication of Chickenpox Infection

Campanelli

Kaya²,

Ozsahin³

et al. 2004

Dermatology

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“…In 1999, Ieko et al (34,35) reported that ␤ 2 GPI exerted a dose-dependent enhancement of t-PA activity in the presence of PAI-1, and that addition of EY1C8 patient-derived monoclonal aCL reduced t-PA activity by ϳ45% in a mixture of t-PA (3.6 U/ml), PAI-1 (7.1 ng/ml), and ␤2GPI (3.8 M). In 2000, Cugno et al (36) showed that of 39 patients with primary APS, three had high titers of IgG Ab against t-PA, and four had high titers of Ab against fibrin-bound t-PA, which is the physiologically active form of t-PA.…”

Section: Discussionmentioning

confidence: 99%

Identification of Anti-Plasmin Antibodies in the Antiphospholipid Syndrome That Inhibit Degradation of Fibrin

Yang

Hwang

Wang³

et al. 2004

The Journal of Immunology

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The combined presence of anti-phospholipid Ab (aPL) and thrombosis is recognized as the antiphospholipid syndrome (APS). The aPL represent a heterogeneous group of Ab that recognize various phospholipids (PL), PL-binding plasma proteins, and/or PL-protein complexes. Recently, we found the presence of antithrombin Ab in some APS patients and that some of these anti-thrombin Ab could inhibit thrombin inactivation by antithrombin. Considering that thrombin is homologous to plasmin, which dissolves fibrin, we hypothesize that some APS patients may have Ab that react with plasmin, and that some anti-plasmin Ab may interfere with the plasmin-mediated lysis of fibrin clots. To test this hypothesis, we searched for anti-plasmin Ab in APS patients and then studied those found for their effects on the fibrinolytic pathway. The results revealed that seven of 25 (28%) APS patients have IgG anti-plasmin Ab (using the mean OD plus 3 SD of 20 normal controls as the cutoff) and that six of six patient-derived IgG anti–thrombin mAb bind to plasmin with relative Kd values ranging from 5.6 × 10−8 to 1 × 10−6 M. These Kd values probably represent affinities in the higher ranges known for human IgG autoantibodies against protein autoantigens. Of these mAb, one could reduce the plasmin-mediated lysis of fibrin clots. These findings suggest that plasmin may be an important driving Ag for some aPL B cells in APS patients, and that the induced anti-plasmin Ab may act either directly, by binding to plasmin and inhibiting its fibrinolytic activity, or indirectly, by cross-reacting with other homologous proteins in the coagulation cascade to promote thrombosis.

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“…Thus, it will be important to test our monoclonal aCL IgGs in their ability to bind to endothelial cells, [56][57][58] to induce tissue factor expression on monocytes, 59 to interfere with the function of activated Prot C 24,60 and, finally, to help in elaborating a murine in vivo model of thrombosis. "Germline % homology" provides the percentage of nucleotide sequence homology between the Ig V gene and its putative germline.…”

Section: Discussionmentioning

confidence: 99%

The clonal analysis of anticardiolipin antibodies in a single patient with primary antiphospholipid syndrome reveals an extreme antibody heterogeneity

Lieby

Soley

Levallois

et al. 2001

Blood

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The mechanism underlying the prothrombotic state that characterizes the primary antiphospholipid syndrome proves to be difficult to define mainly because of the variety of the phospholipid and protein targets of antiphospholipid antibodies that have been described. Much of the debate is related to the use of polyclonal antibodies during the different antiphospholipid assays. To better describe the antiphospholipid antibodies, a strategy was designed to analyze the reactivity of each one antibody making up the polyclonal anticardiolipin activity, breaking down this reactivity at the clonal level. This was performed in a single patient with primary antiphospholipid syndrome by combining (1) the antigen-specific selection of single cells sorted by flow cytometry using structurally bilayered labeled anionic phospholipids and (2) IntroductionAntiphospholipid autoantibodies (aPLs) 1 are associated with thrombosis, recurrent fetal loss, and thrombocytopenia in patients with antiphospholipid syndrome (APS). [2][3][4] The mechanism of the characteristic prothrombotic state related to aPLs during APS is still under debate. 5 Much of it is related to the definition of the precise nature of aPL specificity, which remains unclear because of the number of possible antigenic targets discovered over the last few years. It is now accepted that plasma proteins play an important role in aPL reactivity. 6,7 The most common protein cofactors are ␤2GP1 8,9 and prothrombin. [10][11][12] Other phospholipid (PL)-binding proteins such as protein C9, protein S9, and annexin V 13 have also been found to have cofactor properties. On one hand, studies have shown that the binding of aPLs to cardiolipin (CL) is enhanced by the addition of one cofactor (␤2GP1, prothombin, protein C, protein S), which suggests that aPLs react to a complex compounded of anionic PLs and a cofactor 8,10,11 or to an epitope that becomes exposed when a protein is bound to a PL. [14][15][16] On the other hand, other studies have shown that aPLs are able to bind directly to immobilized ␤2GP1 [17][18][19] or PT 20,21 in the absence of PL. In addition, some studies have shown that anti-␤2GP1 antibodies (Abs) are primarily associated with thrombosis in APS 22-24 although other reports have involved others Abs as anti-PT 25 or lupus anticoagulant. 26 It appears that most of these difficulties are related to the use of polyclonal Abs (serum or purified immunoglobulin [Ig]) 7,8,10,11 or a few monoclonal IgM 15,27-29 or IgG 30-33 aPLs originating from different patients. We therefore considered it necessary to concentrate our attention on aPL reactivity of each Ab making up the polyclonal aPL reactivity, breaking down this reactivity at the clonal level in a single patient.The major methods currently in use for the production of human monoclonal antibodies (mAbs) are Epstein-Barr virus transformation, 34 mouse-human hybridomas, 35 or human-human hybridomas 36 and fusion of Epstein-Barr virus-transformed B lymphocytes with a malignant cell line. 37 These methods have their dr...

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The Putative Mechanism of Thrombosis in Antiphospholipid Syndrome: Impairment of the Protein C and the Fibrinolytic Systems by Monoclonal Anticardiolipin Antibodies

Cited by 35 publications

References 17 publications

Purpura fulminans in a Child as a Complication of Chickenpox Infection

Purpura fulminans in a Child as a Complication of Chickenpox Infection

Identification of Anti-Plasmin Antibodies in the Antiphospholipid Syndrome That Inhibit Degradation of Fibrin

The clonal analysis of anticardiolipin antibodies in a single patient with primary antiphospholipid syndrome reveals an extreme antibody heterogeneity

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