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

Abstract

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 ...

Functional factor XIII-A is exposed on the stimulated platelet surface

“…68 FXIII-B subunit deficiency results in loss of FXIII-A in plasma, presumed to be the result of instability, [69][70][71] but levels of platelet FXIII-A are normal. 70,72 FXIII-B deficiency is associated with milder symptoms than FXIII-A deficiency in humans 69 and FXIII-B knockout mice. 73 This is thought to be the result of the remaining levels of free FXIII-A in the plasma; however, our results suggest that platelet FXIII-A may also compensate under these circumstances.…”

Novel aspects of factor XIII deficiency

“…In a most recent Japanese study, 11 patients with nonneutralizing anti-FXIII-A autoantibodies were reported as opposed to five with neutralizing antibodies [24 ]. An autoantibody against FXIII-B was first reported in 2009 [28]. It formed a complex with FXIII-B and FXIII-A 2 B 2 and highly accelerated their clearance from the circulation causing life-threatening bleeding complications.…”

“…Demonstration of the binding of the patient's IgG (IgM) to isolated FXIII subunits and FXIII complex in an ELISA or dot blot arrangement is required to diagnose the presence of a nonneutralizing anti-FXIII autoantibody [24 ,28]. To verify the accelerated clearance of FXIII from the circulation, the decrease of FXIII activity/antigen is to be followed by serial measurements following supplementation [27,28]. An example for the diagnosis of nonneutralizing autoantibody is shown in Fig.…”

Autoimmune Hemorrhaphilia Resulting from Autoantibody against the A Subunit of Factor XIII

“…However, we were not able to use rituximab in this case because its use for this disorder is not currently accepted at our hospital. In other previously studies in which steroids, CPA, and CyA were ineffective (11,12), alternative treatments, such as plasmapheresis, immunoglobulin, and rituximab, were used, resulting in increased FXIII activity. In the present case, active bleeding has not recurred since the patient began PSL treatment, which represents clinical remission.…”