An acquired coagulation inhibitor to factor II

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

doi:10.1111/j.1365-2141.1982.tb01966.x

Cited by 23 publications

(6 citation statements)

References 12 publications

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“…The fact that thrombin can be converted into a pure anticoagulant by the single amino acid substitution E229A (Gibbs et al, 1995), together with the description of slow and fast forms of thrombin which favour its anticoagulant and procoagulant actions, respectively (Di Cera et al, 1995), emphasize the finely regulated balance between the procoagulant and anticoagulant roles of this protease. One could envisage how an antibody binding to one domain of the molecule could inhibit the procoagulant effect of thrombin and result in bleeding as reported here and elsewhere (Scully et al, 1982;Sié et al, 1991;La Spada et al, 1995). Alternatively, antibody binding to a different site could enhance the procoagulant activity of thrombin resulting in thrombosis that requires oral anticoagulant therapy (Costa et al, 1992;Arnaud et al, 1994).…”

Section: Figmentioning

confidence: 79%

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Identification of a Monoclonal Thrombin Inhibitor Associated with Multiple Myeloma and a Severe Bleeding Disorder

1997

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Summary.We investigated a patient with a long-standing IgGk monoclonal gammopathy who developed severe haemorrhagic complications. At IgG concentrations of ϳ50 g/l the patient had severe bleeding associated with prolongation of the thrombin time, activated partial thromboplastin time, and reptilase time. Plasmapheresis resulted in improvement in the thrombin time and resolution of bleeding. Depletion of the IgG by absorption of plasma with protein G-Sepharose in vitro resulted in normalization of the thrombin time and reptilase time. The purified IgG bound to immobilized thrombin and immunoprecipitated human a-, b-and g-thrombin but not prothrombin, other vitamin K-dependent coagulation factors, or fibrinogen. Purified IgG at concentrations >1 × 10 ¹2 g/l decreased (ϳ50%) the rate of hydrolysis of a chromogenic substrate by thrombin. Addition of purified IgG to normal pooled plasma at concentrations >1 × 10 ¹2 g/l prolonged the thrombin time and activated partial thromboplastin time, but the reptilase time was prolonged only at IgG concentrations >1 g/l. This finding suggests that at low concentrations the IgG produces a specific antithrombin effect, but at higher concentrations it also affects fibrin polymerization; the combination of these effects probably produced clinical bleeding. This is the first report of a monoclonal antithrombin antibody associated with bleeding in a patient with multiple myeloma.

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Section: Figmentioning

confidence: 79%

“…Specific anti-human thrombin autoantibodies have rarely been described. Four cases have been documented in which a serious bleeding disorder resulted (Scully et al, 1982;Bajaj et al, 1985;Sié et al, 1991;La Spada et al, 1995). In another case the patient developed recurrent arterial thromboses (Costa et al, 1992;Arnaud et al, 1994).…”

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confidence: 99%

Identification of a Monoclonal Thrombin Inhibitor Associated with Multiple Myeloma and a Severe Bleeding Disorder

1997

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“…An acquired IgG inhibitor to Factor I1 [23] should not also be found in the urine, not have significant cooperativity with antithrombin 111, nor lose activity upon incubation with heparinase. The medications administered are not known to induce coagulopathies with the exception of moxalactam which has been reported to depress the vitamin K-dependent coagulation factors and perhaps affect the bleeding time [24]; these effects would not explain the coagulation findings in our patient.…”

Section: Discussionmentioning

confidence: 95%

A heparin‐like anticoagulant in an 8‐month‐old boy with acute monoblastic leukemia

et al. 1984

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An 8-month-old male with acute monoblastic leukemia died during induction chemotherapy of severe bleeding refractory to repeated infusions of platelets and clotting factors. A heparin effect was suggested by prothrombin time (PT) of 26 seconds, partial thromboplastin time (PTT) of 94 seconds, thrombin time 240 seconds, and reptilase time 18.4 seconds, with a fibrinogen of 88 mg/dl. Both plasma mixed with the patient's urine and the patient's plasma had their thrombin times corrected toward normal by both PF4 and protamine. Synergism of the anticoagulant with antithrombin III was demonstrated not only by enhanced inhibition of thrombin but also by an increased rate of formation of thrombin--antithrombin III complexes in the presence of the anticoagulant, which was eliminated by preincubation with heparinase. Since the anticoagulant activity was not found in the blasts themselves, it is presumed that the anticoagulant is heparin/heparan liberated from the endothelial lining by products of the cell destruction secondary to chemotherapy.

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“…In contrast, neutralizing thrombin antibodies rarely occur. In addition to the antibodies induced by the exposure to bovine topical thrombin during surgical procedure (see reference 2 for a review), isolated cases ofantithrombin autoantibodies have been reported in patients with systemic lupus erythematosus (3), liver cirrhosis (4), duodenal ulcer treated with ci-metidine and antiacids (5), or without apparent disease (6). In some instances, these inhibitors have been associated with bleeding symptoms.…”

Section: Introductionmentioning

confidence: 99%

An acquired antithrombin autoantibody directed toward the catalytic center of the enzyme.

Sié

Bezeaud²,

Dupouy³

et al. 1991

J. Clin. Invest.

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Antibody inhibitors against human thrombin are rare and have remained poorly characterized. We report the case of a 40-yrold patient who developed a potent thrombin inhibitor revealed by mild bleeding symptoms and marked prolongation of most laboratory clotting times. After two years of evolution, he died from cerebral hemorrhage. The inhibitor, a polyclonal IgG, was associated with hematological and immunological criteria of autoimmune disorder. Antithrombin IgG was isolated from the patient's plasma by protein A-and thrombin-affinity chromatography. Fab fragments inhibited amidolytic activity of a thrombin, and thrombin-thrombomodulin catalyzed protein C activation with a Ki of -10' M in a noncompetitive manner.Alpha to gamma conversion of thrombin resulted in a moderate loss of affinity for the inhibitor. Upon complex formation of thrombin with staphylocoagulase or a2-macroglobulin (a2M), inhibition was decreased by two orders of magnitude and acquired an apparent competitive character. In Western blot experiments, the antibody reacted with active alpha-thrombin, did not react with chloromethylketone-inhibited thrombin and reacted with a lower affinity with iPr2P-thrombin. The inhibitor did not block thrombin binding to benzamidine-, heparin-, or fibrin-Sepharose, but displaced proflavin from its complex with thrombin. Taken together, these results indicate that the patient's autoantibody recognized a conformational structure which includes, at least in part, the apolar binding site adjacent to the catalytic site of thrombin. (J. Clin. Invest. 1991. 88:290-296.)

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An acquired coagulation inhibitor to factor II

Cited by 23 publications

References 12 publications

Identification of a Monoclonal Thrombin Inhibitor Associated with Multiple Myeloma and a Severe Bleeding Disorder

Identification of a Monoclonal Thrombin Inhibitor Associated with Multiple Myeloma and a Severe Bleeding Disorder

A heparin‐like anticoagulant in an 8‐month‐old boy with acute monoblastic leukemia

An acquired antithrombin autoantibody directed toward the catalytic center of the enzyme.

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