Publications by authors named "Akitada Ichinose"

63 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.
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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.
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http://dx.doi.org/10.1111/hae.14298DOI Listing
April 2021

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

Overshoot of FVIII activity in patients with acquired hemophilia A who achieve complete remission.

Int J Hematol 2020 Apr 14;111(4):544-549. Epub 2020 Jan 14.

Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy for AHA aims to arrest bleeding by eliminating FVIII inhibitors. Factor VIII activity overshoot after complete remission (CR) has been reported anecdotally, but details remain unclear. We retrospectively analyzed data from 17 patients with AHA who achieved CR under immunosuppressive therapy between 2009 and 2019 at Gunma University Hospital. FVIII activity overshoot was defined as ≥ 150%. All 17 patients had low FVIII activity (median 2.1%; range < 1.0-8.9%) due to FVIII inhibition (median 14.7 BU/mL; range 2.0-234.0) and all achieved CR within a median of 39 (range 19-173) days. Overshoot occurred in 11 (64.7%) patients and maximal FVIII activity reached > 200% in six of them. The median duration from CR to overshoot was 13 (range 0-154) days. The FVIII overshoot was transient (72.7%) or persistent (27.3%). Venous thromboembolism developed as a complication of overshoot in one patient due to iliac vein compression by a massive hematoma. Overshoot of FVIII activity after CR occurs more frequently than previously expected in patients with AHA.
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http://dx.doi.org/10.1007/s12185-020-02823-yDOI Listing
April 2020

Coagulation and fibrinolytic features in AL amyloidosis with abnormal bleeding and usefulness of tranexamic acid.

Int J Hematol 2020 Apr 3;111(4):550-558. Epub 2020 Jan 3.

Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi Kanazawa, Ishikawa, 920-8641, Japan.

Abnormal bleeding is sometimes observed in patients with immunoglobulin light chain (AL) amyloidosis. Although several theories have been proposed regarding the pathological causes of the bleeding tendency in AL amyloidosis, many lacked sufficient evidence and full consensus. We conducted a retrospective survey at a single institution to assess bleeding manifestations, methods for evaluating hematological abnormalities, and treatments for bleeding in patients with systemic AL amyloidosis over the past 13 years. The participants were 10 men and 14 women, aged 39-84 years (mean 65 years). The prevalence of bleeding was 29%. Prolonged prothrombin time (PT), elevated plasmin-α2-antiplasmin complex, and factor X deficiency were distinctive to the bleeding group. Two case studies showed that tranexamic acid was effective for treating this hematological condition. However, two patients with normal PT and activated partial thromboplastin time (APTT) also had a bleeding manifestation. The rates of administration of coagulation and fibrinolytic tests were relatively low in the non-bleeding group. Therefore, a close investigation concerning coagulation and fibrinolysis should be performed in every patient with AL amyloidosis regardless of the PT/APTT values. A more careful, comprehensive, and large-scale study is required to reinforce these findings.
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http://dx.doi.org/10.1007/s12185-019-02811-xDOI Listing
April 2020

[Immune-mediated acquired coagulation factor deficiencies: state-of-the-art in diagnosis and management].

Authors:
Akitada Ichinose

Rinsho Ketsueki 2019 ;60(6):667-679

Yamagata University School of Medicine.

Recently, in Japan, the number of patients with autoimmune acquired coagulation factor deficiency (AiCFD) due to anti-coagulation factor autoantibodies has been on the rise. There are several types of such autoantibodies, which can be generated against any coagulation factor: 1) the neutralizing type binds the functional region (s) of a coagulation factor to inhibit its activity (inhibitor type) ; 2) the non-neutralizing type binds the nonfunctional region (s) of a coagulation factor and enhances its clearance from circulation (hyperclearance type) ; 3) the combination of types 1) and 2). Despite clinical manifestations of AiCFD ranging from asymptomatic laboratory abnormalities to fatal exsanguination or even to thromboembolic events, most patients with AiCFD exhibit certain bleeding symptoms. Owing to the major bleeding symptoms of AiCFD not being specific for any particular disease, laboratory tests are essential for the early diagnosis of AiCFD, selection of proper treatment, and assessment of a therapy's efficacy. Because of severe ongoing hemorrhages and anemia, most patients are administered large amounts of the deficient coagulation factors. Moreover, given the rarity of this disease, there is no standardized therapeutic modality for antibody eradication. Most patients receive corticosteroids as first-line immunosuppressive medicines; however, some patients become treatment-resistant or develop a recurrence despite achieving remission once.
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http://dx.doi.org/10.11406/rinketsu.60.667DOI Listing
August 2019

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.
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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.
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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.

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

A discrepancy between prothrombin time and Normotest (Hepaplastintest) results is useful for diagnosis of acquired factor V inhibitors.

Int J Hematol 2018 Aug 2;108(2):145-150. Epub 2018 Apr 2.

Japanese Collaborative Research Group on Autoimmune Haemorrhaphilia Supported by the Japanese Ministry of Health, Labor and Welfare, Yamagata, Japan.

Acquired coagulation factor inhibitors are rare. Among them, coagulation factor V (FV) inhibitor is particularly uncommon and presents with variable clinical manifestations. Certain acquired FV inhibitor patients have only mild bleeding or, in select cases, no symptoms at all, leading to spontaneous recovery. Others have life-threatening bleeding that requires medical attention. Thus, a prompt decision regarding diagnosis and clinical intervention is crucial for such patients. In five acquired FV inhibitor cases treated in our facility, each patient had a malignancy as an underlying disease and all unexpectedly showed prolongation of both prothrombin time (PT) and activated partial thromboplastin time (APTT). They all also displayed a discrepancy between PT and Normotest (Hepaplastintest, HPT) results. All but one patient experienced no bleeding at the time of diagnosis and achieved spontaneous recovery in 1-3 weeks. The patient with bleeding symptoms received plasma exchanges and a platelet transfusion. Useful markers in diagnosing the presence of an acquired FV inhibitor were a sudden prolongation of PT and APTT, and a discrepancy between the PT/APTT and HPT assays. Spontaneous recovery can be expected for patients with only minor bleeding.
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http://dx.doi.org/10.1007/s12185-018-2453-zDOI Listing
August 2018

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

Acquired immune-mediated von Willebrand syndrome accompanied by antiphospholipid syndrome.

Rinsho Ketsueki 2017 ;58(6):613-618

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

Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with laboratory findings resembling those of congenital von Willebrand disease. AvWS usually occurs in association with a variety of underlying disorders, such as lymphoproliferative disease or cardiovascular disease, but autoimmune AvWS is very rare. We now describe the case of a 42-year-old woman with autoimmune AvWS with concurrent antiphospholipid syndrome (APS). The patient was suffering from epistaxis and menorrhagia from few years prior to referral. She was referred to our hospital because of Activated Partial Thromboplastin Time (APTT) prolongation. Autoimmune AvWS was diagnosed as hemostatic and immunological analyses showed very low (<6%) levels of vWF ristocetin cofactor activity, low (6%) levels of vWF antigen and the presence of anti-vWF antibodies (IgG1 and IgG2) as well as antiphospholipid antibodies. Steroid therapy led to prompt AvWS remission, but deep vein thrombosis occurred in the left leg, on day 36 and APS was diagnosed. A combination of steroid and anti-coagulant was given for approximately 3 years. Thrombosis has not recurred; but AvWS re-exacerbated with steroid tapering. This is the first case report of autoimmune AvWS concurrent with APS, and the long-term disease course described here can be beneficial to clinicians.
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http://dx.doi.org/10.11406/rinketsu.58.613DOI Listing
November 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.
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http://dx.doi.org/10.1159/000455938DOI Listing
July 2017

Clinical characteristics and outcomes of acquired hemophilia A: experience at a single center in Japan.

Int J Hematol 2017 Jul 15;106(1):82-89. Epub 2017 Mar 15.

Department of Medicine and Clinical Sciences, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.

Acquired hemophilia A (AHA), which is caused by autoantibodies against coagulation factor VIII (FVIII) is a rare, life-threatening bleeding disorder, the incidence of which appears to be increasing in Japan as the population ages. However, the clinical characteristics, treatment, and outcomes of AHA remain difficult to establish due to the rarity of this disease. We retrospectively analyzed data from 25 patients (median age 73 years; range 24-92 years; male n = 15) diagnosed with AHA between 1999 and 2015 at Gunma University Hospital. We identified autoimmune diseases and malignancy as underlying conditions in four and three patients, respectively. Factor VIII activity was significantly decreased in all patients (median 2.0%; range <1.0-8.0) by FVIII inhibitor (median 47.0 BU/mL; range 2.0-1010). Among 71 bleeding events, subcutaneous or intramuscular hemorrhage was the most prevalent. Seventeen patients required bypassing agents. Twenty-two (91.7%) of 24 patients treated with immunosuppressive agents achieved complete response (CR) during a median of 57.5 days (range 19-714 days). Although three patients (12%) relapsed and seven (28%) died of infection, none of the deaths were related to bleeding. Although most of our patients achieved CR after immunosuppressive therapy, the rate of infection-related mortality was unsatisfactorily high.
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http://dx.doi.org/10.1007/s12185-017-2210-8DOI Listing
July 2017

Late-onset neutropenia after rituximab therapy in patients with autoimmune thrombotic and hemostatic disorders: a single center analysis.

Rinsho Ketsueki 2017 ;58(1):42-46

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

Autoimmune thrombotic and hemostatic disorders, caused by autoantibodies against various factors regulating thrombosis and hemostasis, are rare. Rituximab (RTX) is on occasion used for treating these disorders. Late-onset neutropenia (LON) has been described as a side effect of RTX treatment for patients with hemato-oncological and/or rheumatological diseases but not for those with autoimmune thrombotic and hemostatic disorders. Eleven patients with autoimmune thrombotic and hemostatic disorders received RTX in our institution. Four of these 11 cases (36.4%) developed LON after a median 72.6 days of RTX administration (range 43-122). Three cases required G-CSF, but no severe infections developed.
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http://dx.doi.org/10.11406/rinketsu.58.42DOI Listing
May 2017

Autoimmune acquired factor XIII deficiency due to anti-factor XIII/13 antibodies: A summary of 93 patients.

Blood Rev 2017 01 11;31(1):37-45. Epub 2016 Aug 11.

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

Autoimmune acquired factor XIII (F13) deficiency or autoimmune hemophilia-like disease (hemorrhaphilia) resulted from the generation of anti-F13 antibodies (AH13) is a severe bleeding disorder that occurs mainly in the elderly. Although rare, the number of patients diagnosed with AH13 has recently increased. To improve understanding of this disease, the author summarized 93 ever reported/diagnosed AH13 cases. About 50% of cases were idiopathic. In the remaining half of the patients, autoimmune diseases and malignancies were the most common underlying diseases. Intramuscular and subcutaneous bleeding were the most frequently reported symptoms. Hemorrhage was the cause of death in 13 patients. In 4 patients, the diagnosis was established after hemorrhagic death. Therefore, physicians/hematologists must raise the awareness of AH13 as a life-threatening disease. Most patients were treated with F13 concentrates to arrest bleeding and with prednisolone and cyclophosphamide to eradicate anti-F13 autoantibodies. AH13 cases tend to become chronic and intractable and require close follow-up over an extended period.
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http://dx.doi.org/10.1016/j.blre.2016.08.002DOI Listing
January 2017

Recommendation for ISTH/SSC Criterion 2015 for autoimmune acquired factor XIII/13 deficiency.

Thromb Haemost 2016 Sep 21;116(4):772-774. Epub 2016 Jul 21.

Prof. Akitada Ichinose, MD, PhD, Department of Molecular Patho-Biochemistry, Yamagata University School of Medicine, Yamagata, 990-9585 Japan, Tel.: +81 23 628 5275, Fax: +81 23 628 5280, E-mail:

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http://dx.doi.org/10.1160/TH16-05-0362DOI Listing
September 2016

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

[Development of acquired hemophilia A during maintenance therapy for immune thrombocytopenia].

Rinsho Ketsueki 2016 Apr;57(4):456-60

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

Acquired hemophilia A (AHA) is a rare coagulation disorder caused by autoantibodies against coagulation factor VIII (FVIII). We report herein a very rare case of AHA complicated by immune thrombocytopenia (ITP). A 30-year-old woman was hospitalized with severe thrombocytopenia. Her platelet count was 5,000/μl on admission, at which time APTT was normal. ITP was diagnosed and she was treated with γ-globulin, platelet transfusion, and prednisolone at 1 mg/kg/day. She was discharged after platelet count normalization and prednisolone was tapered to 5 mg/day. During the prednisolone tapering, purpura appeared on both thighs and in the left inguinal region, and APTT was found to be prolonged. She was referred to our hospital for examination of APTT prolongation. FVIII activity was markedly decreased to 7.7% and the FVIII inhibitor was positive (1.5 BU/ml), based on which AHA was diagnosed. We carefully followed this patient without intensification of immunosuppressive therapy for 7 weeks, but her platelet count decreased from 150,000/μl to 70,000/μl and the FVIII inhibitor increased to 4 BU/ml. We therefore increased prednisolone to 30 mg/day, after which her platelet count increased and complete remission of AHA was achieved by day 42. In addition, we examined the relationship of the FVIII inhibitor and FVIII binding antibody in this case.
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http://dx.doi.org/10.11406/rinketsu.57.456DOI Listing
April 2016

[Remission of acquired hemophilia A following radiation therapy for esophageal cancer].

Rinsho Ketsueki 2016 Apr;57(4):451-5

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

Although acquired hemophilia A (AHA) often develops in patients with neoplasms, there are few reports on the efficacy of radiation therapy during the bleeding phase of AHA in the prior literature. We herein present a case of AHA experiencing remission soon after radiation therapy for esophageal cancer. A man in his seventies, who had a history of radical nephrectomy for left renal cell carcinoma, received a diagnosis of esophageal cancer. Three months later, he noticed a right thigh hematoma, and was transferred to our hospital. Laboratory data revealed a marked reduction of coagulation factor VIII (FVIII) activity at 0.9% and the inhibitor to FVIII was detected in his serum at 21.8 BU/ml. Under a diagnosis of AHA, the patient received high-dose oral prednisolone, which failed to achieve disease remission. He then underwent radiation therapy to eradicate the underlying esophageal cancer. Despite tapering of the prednisolone dosage, FVIII inhibitor declined to undetectable levels. In this case, radiation therapy for the underlying cancer was associated with achieving complete remission of AHA.
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http://dx.doi.org/10.11406/rinketsu.57.451DOI Listing
April 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.
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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.
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http://dx.doi.org/10.1007/s12185-015-1917-7DOI Listing
March 2016

[Diagnosis and treatment of acquired factor XIII/13 deficiencies: for all doctors treating the MHLW's designated intractable diseases].

Authors:
Akitada Ichinose

Rinsho Ketsueki 2015 Oct;56(10):2110-22

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

Coagulation factor XIII (FXIII/13) comprises a hetero-tetramer formed by two catalytic A subunits and two carrier B subunits. Inherited/congenital FXIII/13 deficiency is a rare hemorrhagic disease, leading to severe bleeding and recurrent miscarriages. By contrast, acquired FXIII/13 deficiency is common, and is characterized by a secondary decrease in FXIII/13 resulting from its hypo-synthesis and/or hyper-consumption due to primary diseases. Autoimmune hemorrhaphilia--a severe bleeding disorder that occurs mainly in the elderly--results from the generation of anti-FXIII/13 antibodies (AH13). Although this disease is still rare, the number of patients diagnosed with AH13 has recently increased. To improve understanding of this disease, we conducted a nation-wide survey on AH13. We found approximately 50% of cases to be idiopathic. In the remaining half, autoimmune diseases and malignancies were the most common underlying disorders. Intramuscular and subcutaneous bleeding were the most frequently reported symptoms. AH13 patients with intracranial, intra-peritoneal, or retroperitoneal bleeding (s) were prone to hemorrhagic death. Therefore, physicians/hematologists must raise awareness of AH13 as a life-threatening disease. Most patients were treated with FXIII/13 concentrates to arrest bleeding and with prednisolone and cyclophosphamide to eradicate anti-FXIII/13 autoantibodies. AH13 became a 'designated intractable disease of Japan,' and 'Board Certified Hematologists' can now be qualified as designated doctors.
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http://dx.doi.org/10.11406/rinketsu.56.2110DOI Listing
October 2015

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

[Acquired von Willebrand syndrome in a patient with immune thrombocytopenic purpura].

Rinsho Ketsueki 2015 Jul;56(7):901-4

Dept. Hematology Fukuyama Chuo-Hospital.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder similar to inherited von Willebrand disease. We describe a 78-year-old woman with coexistent idiopathic thrombocytopenic purpura (ITP) and AVWS. The patient had once been admitted to our hospital because of cerebral infarction. Her platelet count had been normal at that time. Ten years later, she showed a severe bleeding tendency (platelet count 3.2×10(4)/μl). Analysis of hemostatic parameters showed very low (<6%) von Willebrand factor ristocetin cofactor (vWF: Rco), and low VIII: C (22%), but elevated (276%) von Willebrand antigen. Electrophoretic analysis of plasma showed low levels of the high-molecular weight VWF multimer. The presence of antibodies (IgG1 and IgG4) to VWF was detected by enzyme linked immunosorbent assay (ELISA). Factor XIII activity was 42%. Treatment with corticosteroids did not improve the thrombocytopenia, but did correct the bleeding diathesis. Also, VWF: Rco and VIII: C showed normalization. These findings indicated that the patient had ITP associated with AVWS. All reported cases of AVWS associated with systemic lupus erythematosus were cured by appropriate treatment of the underlying autoimmune disease with prednisone or immunosuppression. This bleeding disorder occurs mainly in patients with lymphoproliferative, myeloproliferative, cardiovascular and immunologic disorders, but no patients with ITP have previously been reported. This patient had the rare presentation of AVWS complicated by ITP and factor XIII deficiency.
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http://dx.doi.org/10.11406/rinketsu.56.901DOI Listing
July 2015

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