Publications by authors named "Masayoshi Souri"

40 Publications

Autoimmune Coagulation Factor X Deficiency as a Rare Acquired Hemorrhagic Disorder: A Literature Review.

Thromb Haemost 2021 Apr 30. Epub 2021 Apr 30.

Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University, Yamagata, Japan.

Coagulation factor X (F10) amplifies the clotting reaction in the middle of the coagulation cascade; and thus, F10 deficiency leads to a bleeding tendency. Isolated acquired F10 deficiency is widely recognized in patients with immunoglobulin light-chain amyloidosis or plasma cell dyscrasias. However, its occurrence as an autoimmune disorder is extremely rare. The Japanese Collaborative Research Group has been conducting a nationwide survey on autoimmune coagulation factor deficiencies (AiCFDs); we recently identified three patients with autoimmune F10 deficiency (AiF10D). Furthermore, an extensive literature search was performed, confirming 26 AiF10D and 28 possible cases. Our study revealed that AiF10D patients were younger than patients with other AiCFDs; AiF10D patients included children and were predominantly male. AiF10D was confirmed as a severe type of bleeding diathesis, although its mortality rate was not high. As AiF10D patients showed only low F10 inhibitor titers, they were considered to have non-neutralizing anti-F10 autoantibodies rather than their neutralizing counterparts. Accordingly, immunological anti-F10 antibody detection is highly recommended. Hemostatic and immunosuppressive therapies may help arrest bleeding and eliminate anti-F10 antibodies, leading to a high recovery rate. However, further investigation is necessary to understand the basic characteristics and proper management of AiF10D owing to the limited number of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1496-8527DOI Listing
April 2021

Pathological coagulation parameters in as many as 54 patients with autoimmune acquired factor XIII deficiency due to anti-factor XIII autoantibodies.

Haemophilia 2021 Apr 12. Epub 2021 Apr 12.

Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan.

Introduction: Autoimmune factor XIII (FXIII) deficiency (AiF13D) due to anti-FXIII autoantibodies is an extremely rare, life-threatening bleeding disorder that mostly occurs in the elderly. The number of patients diagnosed with AiF13D has been increasing in Japan, probably because of the nationwide survey on AiF13D supported by the Japanese Ministry of Health, Labour and Welfare.

Aim: To explore the pathologic characteristics of coagulation parameters in AiF13D.

Methods: AiF13D-suspected cases were consulted, and underwent unified/integrated coagulation screening and were definitively diagnosed as AiF13D separately.

Results: AiF13D patients had lower FXIII antigen levels than non-AiF13D patients, but their values overlapped. Among a series of 22-item screening tests and their resulting parameters, the 'FXIII inhibitory potential' yielded by a 1:1 mixing test of the patient's and healthy control's plasma and its 'residual FXIII activity' in 54 AiF13D cases were most distinguishable from 139 non-AiF13D cases, followed by FXIII activity per se and FXIII-specific activity. While the cross-linked α -plasmin inhibitor level reduced, the levels of D-dimer, fibrin/fibrinogen degradation products and plasmin-plasmin inhibitor complex increased, probably because the patients' haematoma nonspecifically induced secondary fibrinolysis in both AiF13D and non-AiF13D patients.

Conclusion: AiF13D appears to induce a hypocoagulopathy combined with a hyper-fibrinolytic state secondary to severe FXIII deficiency caused by anti-FXIII autoantibodies, and the consequent bleeding further modifies its pathological conditions. In addition, the 1:1 mixing test of FXIII activity was confirmed to be a reliable screening method for AiF13D, especially when its derivative parameter, such as the 'FXIII inhibitory potential' or 'FXIII inhibitory potential ratio', is employed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14298DOI Listing
April 2021

Relationship between social support status and mortality in a community-based population: a prospective observational study (Yamagata study).

BMC Public Health 2020 Oct 29;20(1):1630. Epub 2020 Oct 29.

Global Center of Excellence Program Study Group, Yamagata University School of Medicine, Yamagata, Japan.

Background: Social support, defined as the exchange of support in social relationships, plays a vital role in maintaining healthy behavior and mitigating the effects of stressors. This study investigated whether functional aspect of social support is related to 5-year mortality in health checkup participants.

Methods: This study recruited 16,651 subjects (6797 males, 9854 females). Social support was evaluated using five-component questions: Do you have someone 1) whom you can consult when you are in trouble? 2) whom you can consult when your physical condition is not good? 3) who can help you with daily homework? 4) who can take you to hospital when you don't feel well? and 5) who can take care of you when you are ill in bed? The association between the component of social support and all-cause and cardiovascular mortality was examined using Cox proportional hazard analysis.

Results: The percentage of subjects without social support components was 7.7-15.0%. They were more likely to be male, non-elderly, and living alone. During the follow-up period, there were 166 all-cause and 38 cardiovascular deaths. Cox proportional analysis adjusted for confounders showed that only the lack of support for transportation to hospital was significantly associated with all-cause (hazard ratio [HR] 2.01, 95% confidence interval [CI] 1.26-3.05) and cardiovascular mortality (HR 3.30, 95% CI 1.41-6.87). These associations were stronger in males than females.

Conclusion: This study showed that the lack of social support for transportation to the hospital was independently associated with all-cause and cardiovascular mortality in a community-based population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12889-020-09752-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597005PMC
October 2020

[Successful management of acquired factor V deficiency developing shortly after induction of hemodialysis].

Rinsho Ketsueki 2020 ;61(5):445-450

Department of Hematology, Gunma University Graduate School of Medicine.

Autoimmune factor V deficiency (AiF5D) is caused by autoantibodies to coagulation factor V (FV); its clinical manifestations range from asymptomatic to fatal hemorrhage. Herein, we report the case of a 68-year-old man who was diagnosed with end-stage renal disease at the time of a femoral fracture and developed AiF5D after initiating hemodialysis. A wound infection that occurred after joint replacement was treated with antibiotics; however, it was poorly controlled. One month after the procedure, his coagulation time prolonged. The infection was improved by debridement and antibiotics; however, the coagulation time was not decreased and poor hemostasis at the shunt was still persistent. Because ELISA detected anti-FV-binding IgG with FV activity of <2.8% and FV inhibitor levels were 11.8 BU/ml, AiF5D was diagnosed. Oral prednisolone (PSL) was started. Dialysis was initially performed without anticoagulants, but blood clots were not found in the circuit. Anticoagulants were resumed when the coagulation time decreased. After achieving complete remission, PSL dose was tapered and finally discontinued. Few reports have described the management of AiF5D via dialysis. We consider that our report would be useful for the management of patients with similar manifestations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.61.445DOI Listing
August 2020

Generation and Application of Rat Monoclonal Antibodies Specific for a Human Blood Coagulation Protein: von Willebrand Factor.

Monoclon Antib Immunodiagn Immunother 2019 Jun;38(3):133-136

2 Japanese Collaborative Research Group on Autoimmune Coagulation Factor Deficiencies (JCRG), Yamagata, Japan.

von Willebrand factor (VWF) is a glycoprotein that plays a central role in the initiation of blood coagulation. VWF performs two important functions: it acts as a molecular bridge between platelets and as a carrier for coagulation factor VIII (FVIII). von Willebrand disease (VWD) and acquired von Willebrand syndrome (AVWS) are caused by the absence of and/or abnormality in VWF. The pathophysiology of VWD and AVWS is complex and, therefore, it is difficult to diagnose them by conducting the same laboratory tests in all patients. To develop useful monoclonal antibodies (mAbs) for the diagnosis of VWD and AVWS, rat mAbs against human VWF were generated. Immunoblotting analysis revealed that mAbs recognized the reduced and nonreduced VWF protein and endogenous VWF in normal human plasma. Furthermore, we developed a highly sensitive monoclonal antibody-based sandwich enzyme-linked immunosorbent assay technique. In conclusion, the development of VWF-specific mAbs would be useful in the diagnosis of VWD and AVWS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/mab.2019.0008DOI Listing
June 2019

[Recurrence of acquired factor V inhibitor after four years of remission].

Rinsho Ketsueki 2019;60(1):46-50

Department of Hematology, Gunma University Graduate School of Medicine.

Acquired factor V inhibitor (AFV-I) is a rare bleeding disorder wherein autoantibodies are developed against coagulation factor V (FV). The clinical symptoms are variable, from laboratory abnormalities without bleeding to life-threatening hemorrhage. We report herein the case of a patient with AFV-I with two relapses 4 years after the first remission. A 66-year-old male was diagnosed with AFV-I in March 20XX-4. He was treated with prednisolone (PSL) at 50 mg/day and achieved remission within 1 month. PSL dose was tapered to oral administration of 2.5 mg every other day, and long-term remission was maintained. He had been treated with dual antiplatelet therapy (DAPT) for old myocardial infarction. FV activity was markedly reduced to 3.4%, and FV inhibitor was detected (1.0 BU/ml) in May 20XX. We followed the patient without increasing the treatment dose for 2 months, but no spontaneous improvement was seen. Because DAPT was ongoing, we judged that the bleeding risk was high, although only minor bleeding symptoms appeared. PSL was therefore increased to 40 mg/day in June. FV inhibitor rapidly disappeared. When PSL dose was gradually decreased, FV activity decreased, and subcutaneous bleeding occurred in February 20XX+1. PSL dose was increased again for the second relapse, and the patient achieved remission. Few reports have described recurrent AFV-I, and no cases of two relapses have been reported. We believe that this case report is useful for examining the long-term management of AFV-I.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.60.46DOI Listing
August 2019

Complete remission in a bleeding patient with idiopathic autoimmune factor X deficiency caused by non-neutralizing anti-factor X autoantibody.

Haemophilia 2019 03 20;25(2):e106-e109. Epub 2018 Dec 20.

Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.13675DOI Listing
March 2019

A high titer of acquired factor V inhibitor in a hemodialysis patient who developed arterial thrombosis.

Int J Hematol 2019 Feb 16;109(2):214-220. Epub 2018 Nov 16.

Japanese Collaborative Research Group on Autoimmune Coagulation Factor Deficiencies (JCRG supported by the Japanese Ministry of Health, Labor and Welfare), Yamagata, Japan.

An 87-year-old man with diabetes mellitus was admitted to control recurrent bleeding from hemodialysis puncture sites. He was a smoker and had been diagnosed with arteriosclerosis obliterans. His PT and APTT were markedly prolonged, and all coagulation factors were markedly decreased (factor V [FV] activity < 1%) or below the measurement threshold, with the exception of fibrinogen and factor XIII. Neither PT nor APTT were corrected upon mixing with normal plasma. A high titer of FV inhibitor was found at 415 BU/mL, and anti-FV autoantibody was detected by both immunoblot assay and ELISA. Prednisolone administration and plasma exchange partially improved prolonged PT and APTT and decreased the FV inhibitor level. Five months later, he manifested symptoms of severe ischemia in both legs. Angiography revealed diffuse stenosis downstream of both common iliac arteries. Endovascular therapy was repeated four times, the prednisolone dose was reduced, and low-dose antiplatelet therapy was initiated. After the final successful endovascular therapy, arterial thrombosis was detected using ultrasound and angiography. Aspiration thrombectomy and thrombolytic therapy failed to achieve recanalization, and necrosis of the legs worsened. Despite the severe coagulation abnormalities, vascular interventions should have been performed with regular-dose antiplatelet therapy, as the patient exhibited multiple risk factors for atherothrombosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-018-2561-9DOI Listing
February 2019

Lobar Hemorrhage Induced by Acquired Factor XIII Deficiency in a Patient with Cerebral Amyloid Angiopathy.

J Stroke Cerebrovasc Dis 2017 Oct 8;26(10):e203-e205. Epub 2017 Aug 8.

Department of Molecular Patho-Biochemistry, Yamagata University School, Yamagata, Japan and members of the Japanese Collaborative Research Group (JCRG) on Autoimmune Hemorrha-philia due to Anti-factor XIII Antibodies (AH13).

A 68-year-old man presented with intracranial hemorrhage in the right frontal lobe, which rapidly increased the day after admission. We performed hematoma removal with a biopsy of the cortex around the hematoma. The day after the operation, a subcutaneous hematoma over the craniotomy appeared, and the computed tomography showed a recurrent hemorrhage with an acute subdural hematoma. We were aware of a bleeding tendency, and a detailed hematologic examination by hematologists revealed autoimmune acquired factor XIII deficiency due to an antifactor XIII antibody. Specimens taken around the hematomas were pathologically diagnosed as cerebral amyloid angiopathy (CAA) on immunohistochemical examination. We considered that acquired factor XIII deficiency had induced lobar hemorrhage in the frontal lobe affected with CAA, and the coagulation disorder induced postoperative rebleeding. The patient died from repeated lobar hemorrhage 3 years after the surgery. There is no routine screening coagulation test including the active partial thromboplastin time and the prothrombin time for factor XIII deficiency. It is important for neurologists and neurosurgeons to be aware of this rare disease in patients with a bleeding tendency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.07.009DOI Listing
October 2017

Successful Management of a Patient with Autoimmune Hemorrhaphilia due to Anti-Factor XIII/13 Antibodies Complicated by Pulmonary Thromboembolism.

Acta Haematol 2017 6;137(3):141-147. Epub 2017 Apr 6.

Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.

Autoimmune hemophilia-like disease (hemorrhaphilia) due to anti-factor XIII (FXIII) antibodies (AH13) is a very rare, life-threatening bleeding disorder. A 77-year-old woman developed macrohematuria and a right renal pelvic hematoma. The coagulation times were not prolonged, but FXIII activity and antigen levels were severely and moderately reduced to 9 and 29% of normal values, respectively. Accordingly, the FXIII-specific activity turned out to be low. FXIII inhibitor and anti-FXIII-A subunit autoantibodies were detected by a 1:1 crossmixing test and immunoblot and immunochromatographic assays. She was therefore diagnosed with "definite AH13" and treated with plasma-derived FXIII concentrates to arrest the hemorrhage. In addition to a highly compressed inferior vena cava by a huge renal pelvic hematoma, deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) were identified by systemic computed tomography. The patient was immediately started on anticoagulation therapy with low-dose heparin. Emboli disappeared quickly, probably because under-crosslinked thrombi caused by severe FXIII deficiency are vulnerable to fibrinolysis. After about 1.5 years, anti-FXIII-A subunit autoantibodies still remained despite the use of rituximab, steroid pulse therapy, oral prednisolone, and oral cyclophosphamide treatments. In conclusion, an extremely rare AH13 case complicated by DVT and PE was successfully managed by balancing anticoagulation therapy with hemostatic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000455938DOI Listing
July 2017

Molecular pathogenesis of plasminogen Hakodate: the second Japanese family case of severe type I plasminogen deficiency manifested late-onset multi-organic chronic pseudomembranous mucositis.

J Thromb Thrombolysis 2016 Aug;42(2):218-24

Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata, 990-9585, Japan.

A 64-year-old man first developed ligneous conjunctivitis at the age of 58 years after right pulmonary resection because of suspected cancer; otherwise, he had been healthy. Since then, he began to suffer from various forms of chronic pseudomembranous mucositis. Laboratory tests demonstrated that he had 7.8 % of plasminogen activity and 5.9 % of the normal antigen level. Thus, he was diagnosed as having severe type I plasminogen deficiency, making him the third case in Japan. DNA sequencing and PCR-restriction fragment length polymorphism analyses revealed that this patient was a compound heterozygote of a G-to-A missense mutation (G266E) in exon VIII and a g-to-a mutation at the obligatory splicing acceptor site in intron 12 (IVS12-1g>a). These two mutations were confirmed to be novel. Molecular modeling and splice site strength calculation predicted conformational disorder(s) for the Glu266 mutant and a drastic decrease in splicing efficiency for intron 12, respectively. Western blot analysis demonstrated that the patient contained a small amount of the normal-sized plasminogen protein. Mass spectrometric analysis of the patient's plasminogen revealed a peptide containing the wild-type Gly266 residue and no peptides with mutations at Glu266. However, he had never suffered from thrombosis. Low levels of fibrinogen/fibrin degradation products (FDP), D-dimer, and plasmin-α2-plasmin inhibitor complex clearly indicated a hypo-fibrinolytic condition. However, his plasma concentration of elastase-digested crosslinked FDPs was 4.8 U/mL, suggesting the presence of an on-going plasmin(ogen)-independent "alternative" fibrinolytic system, which may protect the patient from thrombosis. The patient has been free from recurrence of ligneous conjunctivitis for approximately 2.5 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11239-016-1375-yDOI Listing
August 2016

Non-autoimmune combined factor XIII A and B subunit deficiencies in rheumatoid arthritis patients treated with anti-interleukin-6 receptor monoclonal antibody (tocilizumab).

Thromb Res 2016 Apr 26;140:100-105. Epub 2016 Feb 26.

Department of Molecular Patho-Biochemistry & -Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address:

Introduction: Coagulation factor XIII (FXIII) is a plasma fibrin-stabilizing factor comprising A and B subunits (FXIII-A and FXIII-B, respectively) in the form of a heterotetramer (FXIII-A2B2). A humanized monoclonal antibody to the interleukin-6 receptor (tocilizumab, TCZ) has emerged as an effective treatment for rheumatoid arthritis (RA), because it drastically reduces the inflammation of RA. We previously reported that two TCZ-treated RA patients with acquired FXIII deficiency developed pelvic hemorrhage.

Methods: Because TCZ treatment had been shown to be related to low FXIII ammonia release activity and FXIII antigen in the two RA cases, we further examined FXIII-related parameters in 36 TCZ-treated RA patients and compared to 29 healthy controls by employing functional and immunologic assays for FXIII.

Results: FXIII-A antigen and FXIII amine incorporation and ammonia release activities were significantly lower in the TCZ-treated group than the control group. The TCZ-treated group also showed mildly low FXIII-A2B2 and FXIII-B levels, and their fibrinogen levels were the lower limit of normal. A significant correlation between FXIII-B and fibrinogen was observed in the control and the TCZ groups, suggesting a common metabolic mechanism(s) for these two hepatic proteins. Because the specific activities of FXIII were normal and neither anti-FXIII-A nor anti-FXIII-B antibody was detected, the overall low FXIII level may have resulted from its impaired synthesis under an unbalanced cytokine milieu caused by TCZ treatment.

Conclusion: Concomitant deficiencies in multiple hemostatic factors, including FXIII, may lead to an increased risk for hemorrhage in TCZ-treated RA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2016.02.026DOI Listing
April 2016

Successful bypass surgery for esophageal carcinoma under adequate factor XIII/13 replacement therapy in a case of intractable autoimmune hemorrhaphilia due to anti-Factor XIII/13 antibodies.

Int J Hematol 2016 Mar 30;103(3):341-7. Epub 2015 Nov 30.

Division of Hematology/Oncology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.

Autoimmune hemorrhaphilia due to anti-factor XIII (FXIII) antibodies (AH13) is a life-threatening disease associated with high risk of surgical bleeding. Since AH13 occurs mainly in the elderly, patients of AH13 tend to be complicated with other life-threatening diseases that may require surgical procedures. During our nation-wide survey on AH13, supported by the Japanese Ministry of Health, Labor, and Welfare, patients with unexplained bleeding were examined for FXIII-related parameters and anti-FXIII autoantibodies. A 64-year-old man had previously been tentatively diagnosed with AH13 and received immunosuppressive therapies, as FXIII inhibitor was detected by functional cross-mixing studies. About 2 years later, he was definitively diagnosed with AH13, because our immuno-chromatographic test and enzyme-linked immuno-sorbent assay detected FXIII-bound anti-FXIII-A subunit autoantibodies. Since routine endoscopic examination revealed suspected esophageal carcinoma, a preparatory FXIII pharmacokinetic (PK) analysis was performed by infusing FXIII concentrates prior to biopsy. Consequently, biopsy of this lesion was done without bleeding complications. One month later, a second PK study was carried out before surgery, and esophageal bypass surgery was completed successfully under FXIII replacement therapy. Our experience with this case suggests that operations can be performed safely and with confidence even in patients with such life-threatening hemorrhagic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-015-1917-7DOI Listing
March 2016

The plasma levels of protein Z-dependent protease inhibitor increase after gynecological surgery independently of estrogen.

Thromb Res 2015 Nov 26;136(5):980-6. Epub 2015 Sep 26.

Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Electronic address:

Introduction: Protein Z (PZ)-dependent protease inhibitor (ZPI) is a serine protease inhibitor that efficiently inhibits activated factor X when ZPI is in complex with PZ. We previously reported significantly higher concentrations of plasma ZPI (and PZ) in women during normal pregnancy than in non-pregnant women.

Methods: We explored the possible contribution of estrogen to the ZPI levels in patients with or without bilateral oophorectomy (OVX), which induces artificial menopause where blood estrogen levels drastically decrease. One hundred ninety-one pre-menopausal Japanese women who underwent open hysterectomy owing to neoplasms participated in this study and were divided into two groups: 98 OVX and 93 Non-OVX cases. Plasma ZPI was measured by ELISA.

Results And Conclusion: Contrary to our working hypothesis, plasma ZPI levels increased significantly in the OVX group after surgery when compared with the pre-operation levels. When these patients were individually analyzed, their ZPI value also rose significantly from pre-operation to post-operation levels. In contrast, plasma PZ levels remained unchanged. The significantly increased ZPI and unchanged PZ levels were also observed in the Non-OVX group. The increased ZPI levels were not significantly related to 17β-estradiol, luteinizing hormone or follicular stimulating hormone levels, clearly indicating that estrogen did not contribute to the plasma ZPI concentrations. Typical acute phase reactants fibrinogen and C-reactive protein (CRP) were also significantly elevated after surgery in both OVX and Non-OVX groups. However, only weakly significant linear relationships were observed between ZPI and fibrinogen or CRP, indicating the presence of alternative regulatory mechanisms underlying their plasma concentrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2015.09.020DOI Listing
November 2015

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

Intern Med 2015 15;54(18):2383-7. Epub 2015 Sep 15.

Department of Hematology, Tokyo Medical and Dental University, Japan.

A 65-year-old woman was admitted with acute intramuscular hemorrhage of the left gluteus medius and piriformis muscles and associated anemia. Blood tests showed low plasma factor XIII (FXIII) antigen and activity. A cross-mixing test revealed a concave "inhibitor" pattern and anti-FXIII-A subunit antibody was detected. The patient was diagnosed with autoimmune hemorrhaphilia resulting from anti-FXIII antibody. The bleeding has not recurred since the initiation of treatment with oral immunosuppressive agents. Although hemorrhagic acquired FXIII deficiency is a rare disorder, prompt recognition of the underlying mechanism can save lives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.54.4791DOI Listing
March 2016

The Non-catalytic B Subunit of Coagulation Factor XIII Accelerates Fibrin Cross-linking.

J Biol Chem 2015 May 25;290(19):12027-39. Epub 2015 Mar 25.

From the Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585 Japan

Covalent cross-linking of fibrin chains is required for stable blood clot formation, which is catalyzed by coagulation factor XIII (FXIII), a proenzyme of plasma transglutaminase consisting of catalytic A (FXIII-A) and non-catalytic B subunits (FXIII-B). Herein, we demonstrate that FXIII-B accelerates fibrin cross-linking. Depletion of FXIII-B from normal plasma supplemented with a physiological level of recombinant FXIII-A resulted in delayed fibrin cross-linking, reduced incorporation of FXIII-A into fibrin clots, and impaired activation peptide cleavage by thrombin; the addition of recombinant FXIII-B restored normal fibrin cross-linking, FXIII-A incorporation into fibrin clots, and activation peptide cleavage by thrombin. Immunoprecipitation with an anti-fibrinogen antibody revealed an interaction between the FXIII heterotetramer and fibrinogen mediated by FXIII-B and not FXIII-A. FXIII-B probably binds the γ-chain of fibrinogen with its D-domain, which is near the fibrin polymerization pockets, and dissociates from fibrin during or after cross-linking between γ-chains. Thus, FXIII-B plays important roles in the formation of a ternary complex between proenzyme FXIII, prosubstrate fibrinogen, and activator thrombin. Accordingly, congenital or acquired FXIII-B deficiency may result in increased bleeding tendency through impaired fibrin stabilization due to decreased FXIII-A activation by thrombin and secondary FXIII-A deficiency arising from enhanced circulatory clearance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M114.608570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424339PMC
May 2015

Rapid immunochromatographic test for detection of anti-factor XIII A subunit antibodies can diagnose 90 % of cases with autoimmune haemorrhaphilia XIII/13.

Thromb Haemost 2015 Jun 5;113(6):1347-56. Epub 2015 Mar 5.

Akitada Ichinose, MD, PhD, Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585 Japan, Tel.: +81 23 628 5276, Fax: +81 23 628 5280, E-mail:

Autoimmune haemorrhaphilia XIII/13 (AH13) is an acquired life-threatening bleeding disorder due to anti-factor XIII (FXIII) autoantibodies (auto-Abs). AH13 patients may die of haemorrhage without correct diagnosis and proper treatment because of lack of awareness and the absence of rapid easy-to-use tests specific for this disease. Currently, the definitive diagnosis is established by cumbersome and time-consuming laboratory tests such as dot-blot assays and enzyme-linked immunosorbent assays (ELISA), and therefore these tests are generally not carried out. To save AH13 patients' lives, there is an urgent necessity for developing a rapid test for FXIII auto-Abs. We first generated and characterised mouse monoclonal antibodies (mAb) against human FXIII A subunit (FXIII-A), and then developed a rapid immunochromatographic test (ICT) for detection of anti-FXIII-A auto-Abs using one mAb with a dissociation constant of 9.3 × 10⁻¹¹ M. The auto-Ab-FXIII-A complex was captured by the mAb on a nitrocellulose membrane and visualised by Au-conjugated anti-human IgG Ab. Mixing with healthy control plasma improved the detection of auto-Abs in patients having extremely low levels of FXIII-A. The specificity and sensitivity of the ICT were 87 % and 94 %, respectively. We also detected auto-Abs against activated FXIII (FXIIIa) in three patients by pre-converting FXIII to FXIIIa by thrombin treatment. ICT values were significantly inversely correlated with FXIII activity levels, indicating an association between the quantity of anti-FXIII autoantibodies and AH13. This reliable rapid ICT assay can be applied to a point-of-care test to detect anti-FXIII-A auto-Abs, and will contribute to early diagnosis and treatment of AH13.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH14-09-0745DOI Listing
June 2015

Report of a patient with chronic intractable autoimmune hemorrhaphilia due to anti-factor XIII/13 antibodies who died of hemorrhage after sustained clinical remission for 3 years.

Int J Hematol 2015 Jun 8;101(6):598-602. Epub 2015 Feb 8.

Department of Internal Medicine, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan.

Although the incidence of autoimmune hemorrhaphilia due to anti-Factor XIII (FXIII, not FVIII or FXII to avoid confusion) antibodies (AH13) or hemorrhagic "acquired FXIII deficiency due to anti-FXIII autoantibodies" was previously considered rare, it has been on the increase in the twenty-first century, at least in Japan. An 83-year-old woman with an unexplained hemorrhage was admitted to our hospital for intramuscular hematoma and severe anemia. Her FXIII activity was reduced to 10 % of normal; since FXIII inhibitors and anti-FXIII-A subunit autoantibodies were detected, she was definitively diagnosed with AH13. Despite developing cardiac tamponade due to pericardial hemorrhage, she clinically recovered from AH13 after hemostatic therapy with FXIII-concentrates and immunosuppressive treatment with rituximab and cyclophosphamide. However, her FXIII activity remained low and she died of hemorrhage 3.5 years after admission. AH13 patients should be monitored for a prolonged period, as this disease is very likely a chronic intractable hemorrhagic disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-015-1754-8DOI Listing
June 2015

Successful treatment of chronic disseminated intravascular coagulation using recombinant human soluble thrombomodulin in a dialysis patient with dissecting aortic aneurysm.

Rinsho Ketsueki 2014 11;55(11):2300-5

Department of Internal Medicine, Kinan Hospital.

A 62-year-old man had a history of acute aortic dissection (Stanford type A) and had been diagnosed with polycystic kidney disease three years earlier, and then developed end-stage renal failure. He was referred with chief complaints of difficult hemostasis and consecutive hemorrhagic episodes at the puncture site of the shunt soon after dialysis introduction. We suspected chronic disseminated intravascular coagulation (DIC) due to mild thrombocytopenia and a fibrinolytic system abnormality. Plasma factor XIII activity was decreased, but no inhibitor was detected. In addition, contrast-enhanced computed tomography showed exacerbation of a dissecting aortic aneurysm. We finally diagnosed chronic DIC and secondary factor XIII deficiency associated with the aortic aneurysm. We selected treatment involving recombinant human soluble thrombomodulin (rTM) because he was on maintenance dialysis and required long-term follow-up bofore the operation. Hemostatic function improved with regular administration of rTM, and was well-controlled preoperatively.
View Article and Find Full Text PDF

Download full-text PDF

Source
November 2014

Complete remission achieved by steroid pulse therapy following rituximab treatment in a case with autoimmune haemorrhaphilia due to anti-factor XIII antibodies.

Thromb Haemost 2014 Oct 17;112(4):831-3. Epub 2014 Jul 17.

Akitada Ichinose, MD, PhD, Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, 990-2331, Japan, Tel.: +81 23 628 5276, Fax: +81 23 628 5280, E-mail:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH14-04-0323DOI Listing
October 2014

Clot retraction is mediated by factor XIII-dependent fibrin-αIIbβ3-myosin axis in platelet sphingomyelin-rich membrane rafts.

Blood 2013 Nov 3;122(19):3340-8. Epub 2013 Sep 3.

Laboratory of Biomembrane and.

Membrane rafts are spatially and functionally heterogenous in the cell membrane. We observed that lysenin-positive sphingomyelin (SM)-rich rafts are identified histochemically in the central region of adhered platelets where fibrin and myosin are colocalized on activation by thrombin. The clot retraction of SM-depleted platelets from SM synthase knockout mouse was delayed significantly, suggesting that platelet SM-rich rafts are involved in clot retraction. We found that fibrin converted by thrombin translocated immediately in platelet detergent-resistant membrane (DRM) rafts but that from Glanzmann's thrombasthenic platelets failed. The fibrinogen γ-chain C-terminal (residues 144-411) fusion protein translocated to platelet DRM rafts on thrombin activation, but its mutant that was replaced by A398A399 at factor XIII crosslinking sites (Q398Q399) was inhibited. Furthermore, fibrin translocation to DRM rafts was impaired in factor XIII A subunit-deficient mouse platelets, which show impaired clot retraction. In the cytoplasm, myosin translocated concomitantly with fibrin translocation into the DRM raft of thrombin-stimulated platelets. Furthermore, the disruption of SM-rich rafts by methyl-β-cyclodextrin impaired myosin activation and clot retraction. Thus, we propose that clot retraction takes place in SM-rich rafts where a fibrin-αIIbβ3-myosin complex is formed as a primary axis to promote platelet contraction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2013-04-491290DOI Listing
November 2013

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

Blood Coagul Fibrinolysis 2013 Sep;24(6):638-41

Department of Medicine (Hematology), Kobe University Graduate School of Medicine, Kobe, Japan.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MBC.0b013e32835facefDOI Listing
September 2013

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

Thromb Haemost 2013 Apr 14;109(4):661-8. Epub 2013 Feb 14.

Department of Molecular Patho-Biochemistry -Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585 Japan.

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 patient's 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH12-12-0936DOI Listing
April 2013

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

Blood Coagul Fibrinolysis 2013 Jan;24(1):85-9

Department of Hematology, Saiseikai Noe Hospital, 1-3-25 Furuichi, Joto-ku, Osaka, Japan.

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 patient's 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MBC.0b013e328358e8e7DOI Listing
January 2013

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

Int J Hematol 2012 Dec 16;96(6):781-5. Epub 2012 Oct 16.

Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, North 15 West 7, Sapporo, 060-8638, Japan.

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 (52.4 %). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-012-1191-xDOI Listing
December 2012

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

J Biochem 2012 Nov 25;152(5):471-8. Epub 2012 Aug 25.

Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, 990-9585 Japan.

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 yeast's 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jb/mvs088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619964PMC
November 2012

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.

Thromb Res 2012 Sep 25;130(3):506-10. Epub 2012 May 25.

Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.

Introduction: Coagulation 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.

Methods And Results: Two 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.

Conclusion: It 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 patient's family members.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2012.05.003DOI Listing
September 2012

Increase in the plasma levels of protein Z-dependent protease inhibitor in normal pregnancies but not in non-pregnant patients with unexplained recurrent miscarriage.

Thromb Haemost 2012 Mar 25;107(3):507-12. Epub 2012 Jan 25.

Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan.

Protein Z (PZ)-dependent protease inhibitor (ZPI) is a serine protease inhibitor which efficiently inactivates activated factor X, when ZPI is complexed with PZ in plasma. Reduced plasma levels of ZPI and PZ have been reported in association with thrombosis. It has also been reported that PZ increases during pregnancy and that its partial deficiency is related to early pregnancy loss or recurrent miscarriage (RM). However, until now there has been no report on ZPI in pregnancy. To explore the possible role(s) of ZPI in the maintenance of pregnancy, we studied 42 non-pregnant normal women, 32 women with normal pregnancies, and 134 cases of unexplained RM in Japan, as well as 64 non-pregnant normal German females. Plasma ZPI was measured by in-house ELISA. There were significantly higher concentrations of plasma ZPI in normal pregnancies compared to non-pregnant women. The present study also confirmed that both factor X, the major target of ZPI, and protein Z increased during normal pregnancies. This increased ZPI and PZ may counteract the increased activated factor X, which may in turn contribute to the maintenance of normal placental circulation. Plasma ZPI levels were unchanged in non-pregnant RM women, while the plasma PZ level was slightly reduced, a finding consistent with existing reports. The exact relationship between RM and this unaltered ZPI with mild PZ reduction relative to normal pregnancies warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH11-08-0591DOI Listing
March 2012