An Acquired Inhibitor of Fibrin Stabilization Associated With Isoniazid Therapy: Clinical and Biochemical Observations

Abstract

A patient who bled seriously while taking isoniazid was found to have an inhibitor of fibrin stabilization. The bleeding appeared to cease soon after the isoniazid was discontinued, although the plasma still contained potent inhibitor activity. This activity gradually disappeared over several weeks. The inhibitor was precipitated at 50% saturation with ammonium sulfate, migrated in the beta area on zone electrophoresis, and was found in the second peak on Sephadex G-200 gel filtration. Inhibitor activity persisted after heating to 90°C. Fibrinogen isolated from the patient’s plasma lacked factor XIII activity but did not contain measurable inhibitor activity. When the rate of incorporation of 14C-putrescine into casein was utilized to study the kinetics of the inhibitor, it was shown that the inhibitor acted reversibly and that it competed with the amine donor, 14C-putrescine. The mechanism whereby isoniazid led to the development of the inhibitor is unknown.

Bleeding tendency caused by IgG inhibitor to factor XIII, treated successfully by cyclophosphamide

“…According to this classification, the present case belongs to type 11, which does not interfere with the activation step but interferes directly with the enzyme activity of activated factor XIII. So far, four cases of type I1 inhibitor have been reported (Lorand et al, 1968;Otis et al, 1974;Fear et al, 1984: Teruya et al 198h), but the inhibitors were not antibodies in three of the four cases. In only one case (Teruya et al, 1986), the inhibitor was shown to be an antibody which appeared to bind the a' subunit but not the a subunit.…”

“…1972:McDevittetal. 1972: Otis et al 1974Milner et al 1977;Lopaciuk et al, 1978;Teruya et al, 1986). None of these therapeutic manoeuvres, however, significantly ameliorated the bleeding problems except in some drug-induced cases, in which the inhibitor was diminished spontaneously after discontinuing the use of thedrug (Lewis, 1972;Otisetd 1974;Rosenbergetul, 1974;Milner et a!, 1977).…”

“…Bleeding tendency due to the presence of an acquired inhibitor to coagulation factor XI11 is a rare disorder, and only 12 cases have been reported so far (Lewis et al, 1967;Lorand et al, 1968;Godal, 1970;Lewis, 1972;Lorand et al, 1972;McDevitt ct al, 1972;Graham et al, 1973;Otis et al 1974;Rosenberg et al, 1974;Godal & Ly, 1977;Milner et al 1977;Lopaciuk et al, 1978;Shires et al, 1979: Fear et al, 1984Teruya et al, 1986). In 10 of these cases, the emergence of the inhibitor was considered to be related to certain drugs, of which isoniazid is the most common agent with six cases.…”

A reversed activity staining procedure for detection of an acquired antibody against factor XIII in a girl with factor XIII deficiency

“…This antibody could also inhibit the transamidating activity of the preactivated a* enzyme. Otis et al (1974) and Fear et a1 (1984) have described inhibitors which were not immunoglobulins. Furthermore, there are only two reports of patients congenitally deficient in factor XI11 who have developed inhibitors against the fibrincrosslinking system.…”

Diagnosis of factor XIII deficiency

“…The presence of these antibodies has also been reported in a few cases with an underlying disease such as monoclonal gammopathy of undetermined significance, rheumatoid arthritis, and systemic lupus erythematosus. [54][55][56] As these inhibitors are usually associated with severe bleeding diathesis, early diagnosis and management of patients is necessary. Patients developing FXIII inhibitors need to be managed by plasmapheresis or immunosuppressive agents such as corticosteroids and cyclophosphamide as well as replacement therapies, which may result in a reduction of inhibitor titer and improvement of clinical phenotype.…”