An Acquired Inhibitor To Coagulation Factor II

Scully, M F; Ellis, Vincent; Kakkar, Vijay V.; Savidge, G. F.; Williams, Yvette; Sterndale, H.

doi:10.1055/s-0038-1652324

Cited by 8 publications

(16 citation statements)

References 3 publications

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“…6. Results of the present study are compatible with the view that there is no specific region of the heparin chain that is responsible for its interactions with heparin cofactor II (Scully et al, 1987;Petitou et al, 1988). The interaction appears to be mainly determined by charge density and the length of the saccharide chain.…”

Section: Discussionsupporting

confidence: 89%

“…These results relating to the catalytic effects of the higher Mr fractions are in general agreement with work of Griffith & Marbet (1983) and Scully et al (1987). The latter group studied the effects of less well-characterized heparin with narrow Mr range, prepared by gel filtration, on the inhibitor-thrombin reactions.…”

Section: Discussionsupporting

confidence: 80%

“…They found that fragments containing a minimum of 12-14 sugar residues are required for acceleration. There is contradictory information regarding the effects of heparin of different sizes on this reaction (Linhardt et al, 1986;Scully et al, 1987;Petitou et al, 1988;Sie et al, 1988;Maimone & Tollefsen, 1988). This may be caused in part by the heterogeneity of the heparin preparations that have been used.…”

Section: Introductionmentioning

confidence: 99%

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Anti-thrombin activities of heparin. Effect of saccharide chain length on thrombin inhibition by heparin cofactor II and by antithrombin

Bray

Lane

Freyssinet

et al. 1989

Biochemical Journal

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The interactions of two proteinase inhibitors, heparin cofactor II and antithrombin, with thrombin are potentiated by heparin. Using two methods, we have studied the potentiating effects of a series of heparin (poly)saccharides with high affinity for antithrombin and mean Mr ranging from approx. 1700 to 18800. First, catalytic amounts of heparin (poly)saccharide were added to purified systems containing thrombin and either heparin cofactor II or antithrombin. Residual thrombin activity was determined with a chromogenic substrate. It was found that only the higher-Me polysaccharides (Mr greater than 8000) efficiently catalysed thrombin inhibition by heparin cofactor II, there being a progressive catalytic effect with increasing Mr of the polysaccharide. Weak accelerating effects were noted with low-Mr saccharides (Mr less than 8000). This contrasted with the well-characterized interaction of heparin with antithrombin and thrombin, where heparin oligosaccharides of Mr less than 5400 had absolutely no ability to accelerate the reaction, while (poly)saccharides of Mr exceeding 5400 showed rapidly increasing catalytic activity with increasing Mr. Secondly, these and other heparin preparations were added in a wide concentration range to plasma with which '25I-labelled thrombin was then incubated for 30 s. Inhibited thrombin was determined from the distribution of labelled thrombin amongst inhibitor-thrombin complexes, predominantly antithrombinthrombin and heparin cofactor II-thrombin complexes. In this situation, where the inhibitors competed for thrombin and for the (poly)saccharides, it was found that, provided the latter were of high affinity for antithrombin and exceeded a Mr of 5400, thrombin inhibition in plasma was mediated largely through antithrombin. Polysaccharides of Mr exceeding 8000 that were of low affinity for antithrombin accelerated thrombin inhibition in plasma through their interaction with heparin cofactor II. High concentrations of saccharides of M, 1700-5400 exhibited a size-dependent acceleration of thrombin inhibition, not through their interaction with antithrombin, but through their interaction with heparin cofactor II.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-thrombin activities of heparin. Effect of saccharide chain length on thrombin inhibition by heparin cofactor II and by antithrombin

Bray

Lane

Freyssinet

et al. 1989

Biochemical Journal

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“…This relationship between anti‐thrombotic and anti‐hemostatic effects is considered absolute, and results in suboptimal dosing within a narrow therapeutic window. Autoantibody inhibitors of thrombin have been reported, usually associated with exposure to products containing bovine thrombin, and are generally associated with bleeding . Here we describe a randomly acquired anti‐thrombin antibody found in a patient who presented with a traumatic subdural hematoma.…”

Section: Introductionmentioning

confidence: 87%

Discovery and characterization of an antibody directed against exosite I of thrombin

Baglin

Langdown

Frasson

et al. 2016

Journal of Thrombosis and Haemostasis

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Essentials• An IgA paraprotein with anti-thrombin activity was not associated with a severe bleeding phenotype.• This observation challenges the paradigm that anticoagulant therapy necessarily increases bleeding risk.• Characterization of the antibody showed that it specifically binds to thrombin exosite I.• A therapeutic drug with the properties of this antibody might be an antithrombotic that doesn't cause bleeding. Summary. Background:We report the case of a 54-year-old female who presented with a traumatic subdural hemorrhage. Coagulation tests were markedly prolonged due to the presence of an anti-thrombin IgA paraprotein at 3 g L À1 . The patient made a complete recovery and has had no abnormal bleeding during a 7-year follow-up, despite the persistence of the paraprotein. Objectives: To determine how the paraprotein prolonged clotting tests by defining its target and its epitope. Methods: The paraprotein was purified and added to normal pooled plasma for in vitro clotting assays. Binding studies were conducted to determine the affinity of the IgA for thrombin. The Fab was isolated and crystallized with thrombin. Results: The purified IgA was sufficient to confer the patient's in vitro coagulation profile in normal pooled plasma, and was found to bind specifically and with high affinity to thrombin. A crystal structure of the Fab fragment in complex with thrombin revealed an exosite I interaction involving CDRH3 of the antibody. Conclusions: Although the patient originally presented with a subdural bleed, the hematoma resolved without intervention, and no other bleeding event occurred during the subsequent 7 years. During this period, the patient's IgA paraprotein levels have remained constant at 3 g L À1 , suggesting that the presence of a highaffinity, exosite I-directed antibody is consistent with normal hemostasis. A therapeutic derivative of this antibody might therefore permit antithrombotic dose escalation without an associated increase in the risk of bleeding.

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“…Mehrere Patienten mit Thrombininhibitoren wurden beschrieben [60,61,62,63]. Diese Autoantikφrper richten sich nicht gegen die inaktive Vorstufe der Proteinase (Prothrombininhibitoren s.o.)…”

Section: Diagnostik Von Thrombininhibitorenunclassified

Diagnostik und Therapiesteuerung bei erworbenen Faktoreninhibitoren. Diagnostics and Therapy Monitoring in Patients with Acquired Coagulation Factor Inhibitors

Grossmann¹,

Geisen²,

Schwender³

et al. 1999

LaboratoriumsMedizin

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An Acquired Inhibitor To Coagulation Factor II

Cited by 8 publications

References 3 publications

Anti-thrombin activities of heparin. Effect of saccharide chain length on thrombin inhibition by heparin cofactor II and by antithrombin

Anti-thrombin activities of heparin. Effect of saccharide chain length on thrombin inhibition by heparin cofactor II and by antithrombin

Discovery and characterization of an antibody directed against exosite I of thrombin

Diagnostik und Therapiesteuerung bei erworbenen Faktoreninhibitoren. Diagnostics and Therapy Monitoring in Patients with Acquired Coagulation Factor Inhibitors

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