Akitada Ichinose

As many as 12 cases with haemorrhagic acquired factor XIII deficiency due to its inhibitors were recently found in Japan.

As many as 12 cases with haemorrhagic acquired factor XIII deficiency due to its inhibitors were recently found in Japan -

Spontaneous regression of the inhibitor against the coagulation factor XIII A subunit in acquired factor XIII deficiency

Spontaneous regression of the inhibitor against the coagulation factor XIII A subunit in acquired factor XIII deficiency -

Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency

Factor XIII (FXIII) is a fibrin-stabilising factor consisting of catalytic A subunits (FXIII-A) and carrier B subunits (FXIII-B). FXIII-B prevents the fast clearance of FXIII-A from the circulation. Congenital FXIII-A deficiency is a rare bleeding disorder, and congenital FXIII-B deficiency is even rarer. Through our recent nationwide survey on acquired haemophilia-like disease due to anti-FXIII autoantibodies, we newly diagnosed severe congenital FXIII-B deficiency in a Japanese man. He developed thrombocytopenia and gingival bleedings at the age of 73, and his FXIII activity was as low as 10% of the normal. When he suddenly developed spontaneous intramuscular haematoma, the bleeding was arrested by infusing FXIII concentrates. However, his FXIII activity remained around 10% of the normal. At the age of 74, ELISA and western blotting assay unexpectedly revealed complete absence of FXIII-B in the patients plasma. A dot blot assay detected anti-FXIII-B alloantibodies for the first time in this disease, which could be attributed to the infusion of exogenous FXIII. He was found to be homozygous for a Japanese founder-effect mutation of F13B. Repeated infusions of exogenous FXIII for hemostasis increased anti-FXIII-B alloantibodies that resisted FXIII substitution. To the best knowledge of the authors, none of the remaining 10 reported cases of congenital FXIII-B deficiency developed alloantibodies to exogenous FXIII-B of plasma FXIII. An originally mild bleeding phenotype of severe congenital FXIII-B deficiency can be exaggerated by additional acquired conditions. Physicians should consider congenital FXIII-B deficiency when they encounter cases of unexplained bleeding disorders.

A case of acquired FXIII deficiency with severe bleeding symptoms

Summary.u2002 Acquired factor XIII (FXIII) deficiency due to an autoantibody against FXIII is a very rare, yet potentially life‐threatening bleeding disorder. As the standard coagulation tests (prothrombin time and activated partial thromboplastin time) are normal, the specialized tests are required to make an accurate diagnosis. Here, we report a case of acquired FXIII deficiency with severe bleeding symptoms. A 75‐year‐old man was referred to our hospital because of severe bleeding tendency after a tooth extraction. Laboratory findings showed that routine coagulation studies were normal, but factor XIII (FXIII) activity was low (3%). The presence of FXIII inhibitor was detected with dot blotting studies. Although the bleeding tendency was very severe, it was successfully controlled by infusion of FXIII concentrates combined with immunosuppressive treatment (oral prednisolone). Fibrin cross‐linking study showed the significant delay of the γ‐chain dimer and α‐chain polymer formation. Western blotting revealed the marked decrease in FXIII‐A level. The mixing study of FXIII activity measured using amine‐incorporation assay showed the incomplete inhibition pattern. There seems to be little agreement as to the treatment strategy of acquired FXIII deficiency. In this patient, the use of FXIII concentrates was very useful in the initial treatment of bleeding symptom. The use of steroids was also effective in increasing FXIII activity without any serious complications.

Hemorrhagic-acquired factor XIII deficiency associated with tocilizumab for treatment of rheumatoid arthritis

Factor XIII (FXIII) is the final enzyme in the coagulation cascade. Acquired FXIII deficiency is caused by inhibitors of FXIII or decreased synthesis and/or increased consumption of FXIII, which leads to severe bleeding. Recently, we experienced a case of hemorrhagic-acquired factor XIII deficiency that occurred during treatment with the IL-6 inhibitor tocilizumab for rheumatoid arthritis. A 48-year-old man was referred because of right hip pain due to a hematoma. Laboratory findings showed that routine coagulation tests were normal, while FXIII activity was slightly low (52.4xa0%). The patient was successfully treated with plasma-derived factor XIII concentrates. The time course of recovery suggests that tocilizumab might have inhibited FXIII production. To our knowledge, this is the first report of acquired factor XIII deficiency associated with administering of tocilizumab. When recurrent bleeding is seen during administering of tocilizumab, acquired factor XIII deficiency may have been induced, thus attending physicians should consider this disease in a differential diagnosis.

Aggressive fatal case of autoimmune hemorrhaphilia resulting from anti-Factor XIII antibodies.

Factor XIII (FXIII) is a fibrin-stabilizing factor consisting of catalytic A subunits (FXIII-A) and carrier B subunits (FXIII-B). Congenital FXIII deficiency is a rare bleeding disorder. Acquired FXIII deficiency resulting from FXIII hypo-synthesis and/or hyperconsumption is a relatively common disorder in which patients seldom bleed. On the contrary, ‘autoimmune/acquired hemorrhaphilia XIII/13 due to anti-FXIII antibodies (AH13)’ is a rare but life-threatening bleeding disorder. Through a nationwide survey of AH13, we diagnosed aggressive AH13 in a 66-year-old woman. She consulted our department because of a spontaneous hematoma in her hand. After 1.5 months, she also developed an intramuscular hematoma but retained approximately half (52%) of the normal FXIII activities. The patients bleeding symptoms were aggravated to catastrophic massive bleedings in the large abdominal muscles and intrapelvic and intraperitoneal spaces. Two months after the bleeding onset, she died despite undergoing plasma exchange, which was performed because we were deeply suspicious of the presence of an anti-FXIII inhibitor. Seven days after her death, extremely low FXIII activity (6%) and positive data on anti-FXIII inhibitor were reported by a commercial laboratory. Our dot blot assay detected anti-FXIII-A autoantibodies, afterwards. Thus, the diagnosis of aggressive AH13 as early as possible is necessary to save patients’ lives.

Impaired dimer assembly and decreased stability of naturally recurring R260C mutant A subunit for coagulation factor XIII

Factor XIII (FXIII) consists of catalytic A subunits (FXIII-A) and carrier B subunits. Congenital FXIII deficiency is a severe bleeding disorder. We previously identified an R260C missense mutation and an exon-IV deletion in Japanese patients F13A genes. To characterize the molecular basis of this disease, we expressed a wild-type and the mutant FXIII-A in yeast cells for detailed investigation, by taking advantage of yeasts ability for mass protein production. The mutant proteins were expressed less efficiently than the wild-type and considerably aggregated; even their non-aggregated forms became aggregated with time. Ultra-centrifugation and gel-filtration analyses revealed that the mutants were of extremely high-molecular weight, and that the wild-type formed a dimer. Notably, a part of the R260C mutant was found in monomer form. This was consistent with the prediction by molecular modelling that the mutant molecule would lose the electrostatic interaction between the two monomers, leading to their inability to form a dimer. The mutants lost enzymatic activity. The mutants were only partially converted by thrombin to the cleaved form. The wild-type was fully converted and activated. These mutants might have significantly altered conformations, resulting in their aggregation in vitro, and may ultimately lead to FXIII deficiency in vivo as well.

Severe inhibitor-negative acquired factor XIII/13 deficiency with aggressive subdural haemorrhage.

Acquired factor XIII (FXIII) deficiency is a common disease and seldom causes bleeding. However, severe FXIII deficiency may result in life-threatening bleeding. Although the inhibitor against FXIII has recently been focused as the cause of haemorrhagic acquired FXIII deficiency, the pathophysiology of inhibitor-negative cases could also be involved. We report a case of an 85-year-old Japanese man with serious subdural haemorrhage showing a remarkable decreased level of FXIII activity. He also manifested complications of compensated disseminated intravascular coagulation (DIC) with chronic renal failure, abdominal aortic aneurysm (AAA) and right renal carcinoma. Despite the successful evacuation of the haemorrhage, acute subdural haemorrhage subsequently developed that necessitated further craniotomies. Plasma cross-mixing studies and dot blot assay revealed no inhibitors against FXIII. We speculated that the decreased FXIII activity could be mainly due to hyperconsumption by DIC and surgery. Because plasma-derived FXIII concentrates are available to stop bleeding, clinicians should be aware of severe acquired inhibitor-negative FXIII deficiency in cases of unexplained excessive bleeding.

Proteosomal degradation of naturally recurring R260C missense and exon‐IV deletion mutants of factor XIII A‐subunit expressed in mammalian cells

Congenital factor XIII (FXIII) deficiency is a severe bleeding disorder. We previously identified an Arg260Cys missense mutation and an exon‐IV deletion in patients A subunit genes, F13A. To characterize the molecular/cellular basis of this disease, we expressed a wild type and these mutant A subunits in baby hamster kidney (BHK) cells. The mutant proteins were expressed less efficiently than the wild type. These mutants gradually decreased inside BHK cells, whereas the wild type remained largely unchanged. The decline/decrease in these mutants was completely blocked/restored by a potent proteasome inhibitor, MG‐132. This was consistent with the prediction by molecular modelling that the mutant molecules would lose the native structure of wild‐type molecule, leading to their instability and degeneration and ultimately to degradation. These mutants might have significantly altered conformations, resulting in the rapid degradation by the proteasome inside the synthesizing cells, and ultimately leading to FXIII deficiency.

Molecular modeling predicts structural changes in the A subunit of factor XIII caused by two novel mutations identified in a neonate with severe congenital factor XIII deficiency

INTRODUCTIONnCoagulation factor XIII (FXIII) is a fibrin-stabilizing factor, which contributes to hemostasis, wound healing, and maintenance of pregnancy. Accordingly, patients with congenital FXIII deficiency manifest a life-long bleeding tendency, abnormal wound healing and recurrent miscarriage. In order to understand the molecular mechanisms of congenital FXIII deficiency, genetic analysis and molecular modeling were carried out in a Japanese male neonate with severe FXIII deficiency.nnnMETHODS AND RESULTSnTwo novel mutations, Y204Stop (or Y204X, TAT to TAA) and S708R (AGC to AGG), were heterozygously identified by nucleotide sequencing analysis in exons V and XV of the gene for the A subunit of FXIII (FXIII-A). Y204X and S708R would lead to nonsense mediated mRNA decay and misfolding of the FXIII-A molecule, respectively. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, the presence of these mutations was confirmed both together in the proband and one each separately in either the maternal or paternal sides of his family. In addition, moderately decreased FXIII activity was associated with the presence of either mutation. Molecular modeling predicted that the mutant molecule of S708R would be structurally compromised by the substitution of the Ser with the larger extended bulky and positively charged Arg side-chain.nnnCONCLUSIONnIt is probable that the impaired tertiary structure of the mutant S708R molecule leads to its instability, which is at least in part responsible for the FXIII deficiency of this patient. This is consistent with the fact that the mutations and the reduced FXIII activities co-segregate among the patients family members.