Severe Bleeding due to Factor V Inhibitor after Repeated Operations Using Fibrin Sealant Containing Bovine Thrombin

Muntean, W.; Zenz, Werner; Edlinger, G; Beitzke, A

doi:10.1055/s-0038-1656146

Cited by 33 publications

(27 citation statements)

References 3 publications

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“…However, antibodies to factor V have frequently been found in individuals exposed to topical thrombin 36,37 or to bovine proteins (bovine thrombin or fibrin sealant) during major surgery. [38][39][40] The isolated antifactor V antibody found in our patient has some peculiarity. It is not able to induce prolongation of the clotting time (no neutralizing effect), and because the concentration of factor V found in the patient's plasma was normal, it does not appear to interfere with the clearance of factor V. These characteristics make the antibody presented herein different from other antifactor V antibodies, which are often associated with bleeding manifestations and are directed against the C2 domain of the cofactor.…”

Section: Discussionmentioning

confidence: 68%

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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Section: Discussionmentioning

confidence: 68%

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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“…Experiences from pediatric cardiac surgery describe a variety of complications associated with fibrin sealants. Low cardiac output and sudden asystole [6] have been reported after the first use of the fibrin sealant and the repeated use of fibrin sealants in pediatric reoperations led to major complications [8].…”

Section: Introductionmentioning

confidence: 99%

Fibrin glue in coronary artery bypass grafting operations: casting out the Devil with Beelzebub?

Lamm

Adelhard

Juchem

et al. 2007

European Journal of Cardio-Thoracic Surgery

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“…Nevertheless, many clinics still work with semi-autologous products consisting ofautologous fibrinogen, which is converted to fibrin through bovine thrombin, in some cases the repeated application of bovine thrombin led to severe immunological side effects (BERGUER et al, 1991 ). The development of antibodies against human clotting factors ( MUNTEAN et al, 1997) and anaphylaxis has occurred, and in rare cases the use of bovine thrombin has led to death (NICHOLS et al, 1993). Because of these side effects, ten years ago, bovine thrombin was replaced by human thrombin gained from pooled sources in commercially available fibrin glues.…”

Section: Introductionmentioning

confidence: 99%

Preparation of a pure autologous biodegradable fibrin matrix for tissue engineering

Haisch

Loch

David

et al. 2000

Med. Biol. Eng. Comput.

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Parallel to the growing role of tissue engineering, the need for cell embedding materials, which allow cells to stabilise in a three-dimensional distribution, has increased. Although several substances have been tested, fibrin is thus far the only one that permits the clinical application of cultured tissue. To date, autologous fibrinogen has usually been polymerised with bovine thrombin, which can cause severe immunological side effects. The objective of this study was to explore the practicability of obtaining autologous thrombin from a single patient in an adequate concentration and amount. Fibrinogen was cryoprecipitated from 200 ml of freshly-frozen plasma. Thrombin was isolated from the supernatant through ion-exchange chromatography. The thrombin was first bound to Sephadex A-50 and then eluated using 2 ml of a salt buffer (2.0 M NaCl in 0.015 M trisodiumcitrate, pH 7.0). The activity of the thrombin (51 NIH x ml(-1) to 414 NIH x ml(-1) reached levels comparable to those in commercially available fibrin glues (4-500 NIH x ml(-1)). The study has shown that it is possible to obtain a sufficient amount of autologous thrombin from a single donor to create a fibrin matrix of high efficiency without the risk of immunological and infectious side effects.

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Severe Bleeding due to Factor V Inhibitor after Repeated Operations Using Fibrin Sealant Containing Bovine Thrombin

Cited by 33 publications

References 3 publications

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

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

Fibrin glue in coronary artery bypass grafting operations: casting out the Devil with Beelzebub?

Preparation of a pure autologous biodegradable fibrin matrix for tissue engineering

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