Factor V inhibitor in thrombosis

Kapur, Ashok; Kelsey, P R; Isaacs, Peter

doi:10.1002/ajh.2830420410

Cited by 43 publications

(34 citation statements)

References 11 publications

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“…In this context, it is noteworthy that we found two of our mAbs against factor V to partially inhibit the APC cofactor activity directly in plasma, whereas they did not affect the procoagulant activity of factor V (unpublished observation). Moreover, in a recent report, a patient with a severe thrombotic disease was described as having an acquired autoantibody against factor V (the epitope for the antibody was not localized) (17). Our present results provide an explanation for the apparent paradox of a patient with an antibody against factor V having a thrombotic rather than a bleeding diathesis.…”

Section: Discussionsupporting

confidence: 50%

Inherited resistance to activated protein C iscorrected by anticoagulant cofactor activity found to be a property of factorV.

Dahlbäck

Hildebrand

1994

Proc. Natl. Acad. Sci. U.S.A.

337

172

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Section: Discussionsupporting

confidence: 50%

Inherited resistance to activated protein C iscorrected by anticoagulant cofactor activity found to be a property of factorV.

Dahlbäck

Hildebrand

1994

Proc. Natl. Acad. Sci. U.S.A.

337

172

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“…12 Only 3 cases of patients with antibodies to factor V have been associated with thrombotic events. However, 2 of the 3 cases had an autoimmune syndrome where lupuslike anticoagulant activity was demonstrated in association with anticardiolipin antibodies, 13,14 whereas the antifactor V antibody in the third case was associated with Sjögren syndrome. 15 It is interesting to note that in all 3 cases prolongation of the basal clotting time was present, suggesting an interference with the procoagulant function of factor V. It has been demonstrated in one case (Sjögren syndrome 15 ) that although the antibody in vitro did not inhibit activated protein C activity toward factor Va, it was able to inhibit the procoagulant function of factor V. It is well established that the binding to a membrane surface is necessary for both normal procoagulant expression of factor Va cofactor activity as well as efficient down-regulation of its activity by APC.…”

Section: Discussionmentioning

confidence: 99%

“…Only 3 antifactor V antibodies have been demonstrated to cause thrombotic manifestations. However, these antibodies were not well characterized and, whereas 2 of them were associated with lupuslike symptoms, 13,14 the third antifactor V antibody was associated with Sjögren syndrome. 15 In the present manuscript, we present data from an individual with an antifactor V antibody that interferes with the anticoagulant pathway of blood coagulation.…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations

Kalafatis

Simioni²,

Tormene³

et al. 2002

Blood

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A 44-year-old woman with a history of severe thrombotic manifestations presented with a markedly reduced activated protein C-sensitivity ratio (APC-SR). DNA sequencing of and around the regions encoding the APC cleavage sites in the factor Va molecule excluded the presence of the factor VLeiden mutation and of other known genetic mutations. No antiphospholipid antibodies were present in the patient's plasma and both prothrombin time and activated partial thromboplastin time were normal. The total immunoglobulin fraction was isolated from the patient's plasma and found to induce severe APC resistance when added to normal plasma and to factor V-deficient plasma supplemented with increasing concentrations of factor V. Immunoblotting and immunoprecipitation experiments with the total immunoglobulin fraction purified from the patient's plasma demonstrated that the antibody recognizes factor V, is polyclonal, and has conformational epitopes on the entire factor V molecule (heavy and light chains, and B region). Thus, the immunoglobulin fraction interferes with the anticoagulant pathway involving factor V. The inhibitor was isolated by sequential affinity chromatography on protein G-Sepharose and factor V-Sepharose. The isolated immunoglobulin fraction inhibited factor Va inactivation by APC because of impaired cleavage at Arg306 and Arg506 of the heavy chain of the cofactor. The isolated immunoglobulin fraction was also found to inhibit the cofactor effect of factor V for the inactivation of factor VIII by the APC/ protein S complex. Our data provide for the first time the demonstration of an antifactor V antibody not related to the presence of antiphospholipid antibodies, which is responsible for thrombotic rather than hemorrhagic symptoms. IntroductionCoagulation factor V circulates in plasma as a large single-chain protein with a M r 330 000. 1,2 ␣-Thrombin cleaves single-chain factor V to give rise to the active cofactor (factor Va) and to 2 heavily glycosylated activation fragments. The factor Va resulting from ␣-thrombin cleavage of human factor V is composed of a heavy chain of M r 105 000 containing the NH 2 -terminal part of the factor V molecule (A1-A2 domains) and a light chain of M r 74 000 that is derived from the COOH-terminal end of the cofactor (A3-C1-C2 domains). Once formed, ␣-thrombin binds to the endothelial cell receptor thrombomodulin and initiates the protein C pathway leading to the formation of APC. Proteolytic cleavage of factor Va by APC is required for complete inactivation of the cofactor and arrest of its contribution to the procoagulant process. 3 Factor Va is inactivated by activated protein C (APC) following 3 cleavages of the heavy chain: Arg506, Arg306, and Arg679. Cleavage at Arg306 efficiently occurs on the membrane-bound cofactor and is responsible for complete inactivation of factor Va. 3 Thus, irregularities in the mechanism of inactivation of factor Va by APC are associated with thrombotic episodes because of sustained prothrombin activation.Individuals with a 1691GϾA substitu...

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“…Anecdotally, a lupus anticoagulant specific for factor X has been identified in a patient with anticardiolipin antibodies and a hemorrhagic diathesis (Dr. D. Triplett: personal communication). Two patients with thrombosis, lupus anticoagulants, and acquired factor V inhibitors have been described (59,60).…”

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confidence: 99%

Immunology of the antiphospholipid antibody syndrome

Roubey

1996

Arthritis & Rheumatism

286

170

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Like the femme fatale in The Beatles' Rocky Raccoon, antiphospholipid antibodies (aPL) and the syndrome with which they are associated (thrombosis, recurrent fetal deaths, thrombocytopenia) have attracted considerable attention despite a serious nomenclature problem. Along with increasing experience in the optimal management of patients with the aPL syndrome and growing evidence that autoantibodies may play a direct pathophysiologic role, research over the past several years demonstrates that a large proportion of "antiphospholipid" autoantibodies do not, in fact, recognize phospholipids. These new data indicate that the antigenic targets of antibodies detected in conventional anticardiolipin and lupus anticoagulant assays are phospholipid-binding plasma proteins, most notably, &-glycoprotein I (&GPI) and prothrombin or complexes of these proteins with phospholipids. Further, autoantibodies to other phospholipid-binding plasma proteins and certain molecules expressed on vascular endothelium may also be associated with the antiphospholipid antibody syndrome (APS) although they are not detectable in standard aPL assays.This review summarizes recent information on the specificities of autoantibodies associated with APS and discusses the insights these data offer into the potential role of autoantibodies in the syndrome's pathophysiology. Antigenic specificities of aPL: historical perspective Current concepts of aPL date to the early part of this century and the development of nontreponemal serologic tests for syphilis (STS). In the early 1940s, Mary Pangborn identified the antigenic component of the tissue extracts used in these tests as a novel anionic phospholipid, which she named cardiolipin (1). As a result of widespread population screening for syphilis, in the 1950s it was observed that individuals with chronically false-positive STS results, when followed up for many years, often developed systemic lupus erythematosus (SLE) (2). False-positive STS results were also noted to be present in early reports of SLE patients with acquired inhibitors of in vitro phospholipid-dependent coagulation tests, in particular, the activation of prothrombin (3). Laurel1 and Nilsson investigated this association and suggested that the anticoagulant effect and the positive reactions with phospholipid antigen were ascribable to the same causal factor (4). Additional support for the hypothesis that these acquired coagulation inhibitors were directed against phospholipid came from studies demonstrating that the anticoagulant effect was enhanced when the phospholipid in the test system was diluted (5).In contrast, a number of key features of the inhibitors, subsequently termed lupus anticoagulants (6), were not compatible with phospholipid specificity and suggested an important role of plasma proteins. First, certain lupus anticoagulants were species specific, for example, they prolonged coagulation reactions of human plasma but not bovine plasma (7). Second, certain lupus anticoagulants did not inhibit phospholipid-dependent reacti...

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Factor V inhibitor in thrombosis

Cited by 43 publications

References 11 publications

Inherited resistance to activated protein C iscorrected by anticoagulant cofactor activity found to be a property of factorV.

Inherited resistance to activated protein C iscorrected by anticoagulant cofactor activity found to be a property of factorV.

Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations

Immunology of the antiphospholipid antibody syndrome

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