Differences between Type I Autoimmune Inhibitors of Fibrin Stabilization in Two Patients with Severe Hemorrhagic Disorder

Łopaciuk, S; Bykowska, Ksenia; McDonagh, Jan; McDonagh, R. P.; Yount, William J.; Fuller, C. Randall; Cooperstein, Lawrence A.; Gray, A.; Lóránd, L.

doi:10.1172/jci109035

Cited by 35 publications

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References 30 publications

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“…Inhibitors arising from replacement therapy in congenital FXIII deficiency are rare, and inhibitors causing acquired FXIII deficiency are 10 times as rare as congenital FXIII deficiency [8]. Acquired FXIII deficiency has been reported with autoimmune disorders [9], and medications including phenytoin [10], isoniazid [11,12], penicillin [13] and procainamide [14]. FXIII inhibitors complicating amiodarone therapy have not been reported, and in our patient with inactive rheumatoid arthritis, the inhibitor persisted after discontinuing amiodarone.…”

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confidence: 80%

Prophylactic and perioperative replacement therapy for acquired factor XIII deficiency

Lim

Moffat

Hayward

2004

Journal of Thrombosis and Haemostasis

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To cite this article: Lim W, Moffat K, Hayward CPM. Prophylactic and perioperative replacement therapy for acquired factor XIII deficiency. J Thromb Haemost 2004; 2: 1017-19. Acquired factor (F)XIII deficiency is a rare coagulation disorder with limited information on using laboratory assays to guide management. We encountered unique monitoring and therapeutic challenges while managing a 73-year-old man with acquired FXIII deficiency. He presented with an extensive leg hematoma after receiving low-molecular-weight heparin for a suspected calf vein thrombosis. Two years earlier, he had developed a leg hematoma while on warfarin, which was discontinued. His medical history included inactive rheumatoid arthritis, stable angina, and paroxysmal atrial fibrillation on amiodarone. There was no family or prior bleeding history. He had previously undergone tonsillectomy, cholecystectomy and dental extractions without incident. Coagulation tests indicated an isolated deficiency of FXIII, with no FXIII activity detectable by the urea clot solubility assay [1,2] , twice weekly). A portacath was placed for home replacement therapy. Amiodarone was discontinued due to concerns about a drug-induced FXIII inhibitor.Six months later, the patient developed increasing angina. Angiography revealed a 90% stenosis of the left anterior descending coronary artery and a single coronary artery bypass graft was recommended. His FXIII inhibitor titer remained low (< 2 BU) and preoperative FXIII survival studies confirmed accelerated FXIII clearance, with more rapid decay of FXIII activity compared with FXIIIA antigen (Fig. 1A). Bypass surgery was done using off-pump, beating heart surgery to minimize risks of a postoperative coagulopathy. Perioperatively, FXIII levels were monitored using the Berichrom assay, as no other rapid commercial assays were available. He was given 2500 U FXIII (42 U kg ) immediately before and after surgery, and again on postoperative days 1-3, 5-7 and 9, before resuming his usual prophylaxis (2500 U twice weekly), which normalized his FXIII activity during surgery and maintained levels above 0.40 U mL )1 for 7 days postoperatively (Fig. 1B). No abnormal bleeding occurred and he recovered fully without complications. Over the subsequent 38 months, his FXIII inhibitor has remained < 2 BU and he has been maintained on lower doses of FXIII prophylaxis and aspirin 80 mg daily, without further angina or serious bleeding.He had a few minor bleeds when his FXIII prophylaxis was reduced to the point that no predose FXIII activity was detectable by urea clot solubility assays, but this resolved when his prophylaxis was adjusted to provide residual FXIII activity (1750 U, 29 U kg )1 weekly).FXIII is important for stabilizing fibrin and making clots less susceptible to plasmin lysis [5][6][7]. Inhibitors arising from replacement therapy in congenital FXIII deficiency are rare, and inhibitors causing acquired FXIII deficiency are 10 times as rare as congenital FXIII deficiency [8]. Acquired FXIII deficiency has been report...

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confidence: 80%

Prophylactic and perioperative replacement therapy for acquired factor XIII deficiency

Lim

Moffat

Hayward

2004

Journal of Thrombosis and Haemostasis

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“…In a few cases, the autoantibody was characterized and classified into subgroups according to its inhibition of FXIII activation, FXIIIa activity, or binding to fibrin. [10][11][12][13][14][15] In about one third of the cases the autoantibody was associated with systemic lupus erythematosus (SLE). No report on an autoantibody directed against FXIII-B has been published so far.…”

Section: Introductionmentioning

confidence: 99%

Severe bleeding complications caused by an autoantibody against the B subunit of plasma factor XIII: a novel form of acquired factor XIII deficiency

Ajzner

Schlammadinger

Kerényi

et al. 2009

Blood

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Acquired factor XIII (FXIII) deficiency due to autoantibody against FXIII is a very rare severe hemorrhagic diathesis. Antibodies directed against the A subunit of FXIII, which interfere with different functions of FXIII, have been described. Here, for the first time, we report an autoantibody against the B subunit of FXIII (FXIII-B) that caused lifethreatening bleeding in a patient with systemic lupus erythematosus. FXIII activity, FXIII-A 2 B 2 complex, and individual FXIII subunits were undetectable in the plasma, whereas platelet FXIII activity and antigen were normal. Neither FXIII activation nor its activity was inhibited by the antibody, which bound to structural epitope(s) on both free and complexed FXIII-B. The autoantibody highly accelerated the elimination of FXIII from the circulation. FXIII supplementation combined with immunosuppressive therapy, plasmapheresis, immunoglobulin, and anti-CD20 treatment resulted in the patient's recovery. FXIII levels returned to around 20% at discharge and after gradual increase the levels stabilized above 50%. IntroductionBlood coagulation factor XIII (FXIII) is a protransglutaminase of tetrameric structure (FXIII-A 2 B 2 ). 1,2 Its potentially active A subunit (FXIII-A) is synthesized in cells of bone marrow origin; it is also present in platelets and monocytes/macrophages in dimeric form (FXIII-A 2 ). The noncatalytic B subunit (FXIII-B) is in excess and it is essential for the stabilization of FXIII-A 2 in plasmatic conditions. FXIII is converted into an active transglutaminase (FXIIIa) by limited proteolysis of FXIII-A and by Ca 2ϩ -induced dissociation of FXIII-B. Cross-linking of fibrin ␣-and ␥-chains and ␣ 2 -plasmin inhibitor to fibrin by FXIIIa stabilizes fibrin and protects it from prompt elimination by plasmin. 3 Inherited FXIII-A deficiency is a severe bleeding diathesis with the high risk of intracranial bleeding in nonsupplemented patients. 4 Only 5 cases of inherited FXIII-B deficiency with mild-to-moderate bleeding tendency have been reported. [5][6][7][8] In the absence of FXIII-B, plasma FXIII activity and FXIII-A concentration were considerably decreased, whereas in platelets a normal amount of FXIII-A was measured. 9 Thirty-six cases of severe FXIII deficiency due to an autoantibody against FXIII-A have been reported. In a few cases, the autoantibody was characterized and classified into subgroups according to its inhibition of FXIII activation, FXIIIa activity, or binding to fibrin. [10][11][12][13][14][15] In about one third of the cases the autoantibody was associated with systemic lupus erythematosus (SLE). No report on an autoantibody directed against FXIII-B has been published so far. MethodsA 28-year-old woman suffering from SLE with end-stage kidney disease was on hemodialysis. For preparation of cubital fistula she was admitted to a county hospital. In the proximity of the surgical wound, hematomas developed that were explored. The wounds showed no tendency of healing and remained open. A few days later extensive intramuscular hematoma ...

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“…Our patient had multiple drug therapy and was on thyroid replacement but never received isoniazid. The role of isoniazid in the formation of an inhibitor is speculative, but it has been suggested that it may covalently modify the structure of FXIII and result in a breakdown of immune tolerance to this protein [11], 2 of the inhibitors reported produced a quantitative abnormality of fibrin crosslinking with absent a-polymerisation and decreased y-y-dimerisation [10,12]. In our patient fibrin cross-linking was highly ab normal.…”

Section: Discussionmentioning

confidence: 63%

An Acquired Inhibitor of Factor XIII with a Qualitative Abnormality of Fibrin Cross-Linking

Fear¹,

Miloszewski²,

Losowsky³

1984

Acta Haematol

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A patient with an acquired inhibitor to factor XIII is reported. The patient’s plasma produced a profound inhibition of factor XIII activity in normal plasma measured by a dansylcadaverine casein assay and stimulated a very abnormal pattern of fibrin cross-linking, not normally seen with factor XIII. Partial characterisation of the inhibitor suggests that it is heat stable and not an immunoglobulin.

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Differences between Type I Autoimmune Inhibitors of Fibrin Stabilization in Two Patients with Severe Hemorrhagic Disorder

Cited by 35 publications

References 30 publications

Prophylactic and perioperative replacement therapy for acquired factor XIII deficiency

Prophylactic and perioperative replacement therapy for acquired factor XIII deficiency

Severe bleeding complications caused by an autoantibody against the B subunit of plasma factor XIII: a novel form of acquired factor XIII deficiency

An Acquired Inhibitor of Factor XIII with a Qualitative Abnormality of Fibrin Cross-Linking

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