Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature

We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4+ lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4+ plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4+ plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10-2 [5.7 10-4-1.79 10-1]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10-5 [2.0 10-5-6.0 10-5]), a polyclonal setting in which all IgG4+ plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10-3 at diagnosis and 1.0 10-3 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4+ plasma cell proliferation.

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Acquired Hemophilia a Secondary to Autoimmune Pancreatitis with Elevated IG4

Thrombosis & Haemostasis: Research ◽

10.26420/thrombhaemostres.2021.1058 ◽

2021 ◽

Vol 5 (2) ◽

Author(s):

Li Y ◽

◽

Li J ◽

He H ◽

Cai R ◽

...

Keyword(s):

Factor Viii ◽

Hormone Therapy ◽

Rare Disease ◽

Plasma Exchange ◽

Autoimmune Pancreatitis ◽

Hemophilia A ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Related Disease ◽

Igg4 Related Disease

Acquired Hemophilia A (AHA) is a rare disease resulting from autoantibodies against Factor VIII (FVIII) that leads to bleeding. AHA associated with IgG4 related diseases is even rarer. The patient was diagnosed with IgG4 associated autoimmune pancreatitis in January 2019, and the condition improved after two hospitalizations. However, 22 months later, the patient was admitted to hospital due to generalized bleeding points. He was diagnosed with AHA and improved after hormone therapy and plasma exchange. Although IgG4 is associated with IgG4-related disease and AHA, its relevance to the etiology of both diseases is not well understood.

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Acquired hemophilia A and plasma cell neoplasms: a case report and review of the literature

Journal of Medical Case Reports ◽

10.1186/s13256-020-02505-7 ◽

2020 ◽

Vol 14 (1) ◽

Author(s):

Katarzyna A. Jalowiec ◽

Martin Andres ◽

Behrouz Mansouri Taleghani ◽

Albulena Musa ◽

Martina Dickenmann ◽

...

Keyword(s):

Factor Viii ◽

Plasma Cell ◽

Hemophilia A ◽

High Titer ◽

Coagulation Factor ◽

Laboratory Diagnostics ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Plasma Cell Neoplasm ◽

Cell Neoplasm

Abstract Background Acquired hemophilia A is a rare autoimmune disease with clinically often significant bleeding diathesis resulting from circulating autoantibodies inhibiting coagulation factor VIII. Half of acquired hemophilia A cases are associated with an underlying disorder, such as autoimmune diseases, cancer, or use of certain drugs, or occur during pregnancy and in the postpartum period. In the other half, no underlying cause is identified. An association of acquired hemophilia A with plasma cell neoplasm seems to be extremely rare. Case presentation We describe a case of a 77-year-old Swiss Caucasian man who was diagnosed with acquired hemophilia A and smoldering multiple myeloma as an underlying cause. Acquired hemophilia A was treated with prednisolone, cyclophosphamide, and immunoadsorption. Extensive workup revealed a plasma cell neoplasm as the only disorder associated with or underlying the acquired hemophilia A. For long-term control of acquired hemophilia A, we considered treatment of the plasma cell neoplasm necessary, and a VRD (bortezomib, lenalidomide, and dexamethasone) regimen was initiated. Due to multiple complications, VRD was reduced to VRD-lite after two cycles. After nine cycles of induction therapy and five cycles of consolidation therapy, the patient is in complete remission of his acquired hemophilia A and very good partial remission of the plasma cell neoplasm. We conducted a literature review to identify additional cases of this rare association and identified 15 other cases. Case descriptions, including the sequence of occurrence of acquired hemophilia A and plasma cell neoplasm , treatment, evolution, and outcome are presented. Discussion and conclusions Our case, together with 15 other cases described in the literature, underscore the possibility of plasma cell neoplasm as an underlying cause of acquired hemophilia A. Physicians should consider including protein electrophoresis, immunofixation, and analysis of free light chains in laboratory diagnostics when treating a patient with acquired hemophilia A. The occurrence of excessive and unexplained bleeding in patients diagnosed with plasma cell neoplasm should raise suspicion of secondary acquired hemophilia A and trigger the request for coagulation tests, particularly in patients treated with immunomodulatory drugs such as thalidomide or lenalidomide. Additionally, early intervention with immunoadsorption can be lifesaving in cases with high-titer factor VIII inhibitors, especially when surgical interventions are necessary.

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IgG4-related intracranial disease

The Neuroradiology Journal ◽

10.1177/1971400918806323 ◽

2018 ◽

Vol 32 (1) ◽

pp. 29-35 ◽

Cited By ~ 6

Author(s):

Shahine Goulam-Houssein ◽

Jeffrey L Grenville ◽

Katerina Mastrocostas ◽

David G Munoz ◽

Amy Lin ◽

...

Keyword(s):

Plasma Cells ◽

Surgical Intervention ◽

Case Series ◽

Hypertrophic Pachymeningitis ◽

Diagnostic Challenge ◽

Perineural Spread ◽

Related Disease ◽

The Third ◽

Igg4 Related Disease ◽

Intracranial Involvement

IgG4-related disease (IgG4-RD) is a multi-organ chronic inflammatory process caused by infiltration of IgG4-positive plasma cells in one or more organs. Intracranial involvement has only recently become better recognized. Our case series adds to the growing literature on the varying presentations of intracranial IgG4 by describing the clinical and imaging findings of three patients who presented to our institution with intracranial involvement. Our first patient presented with a mass-forming IgG4 pachymeningitis mimicking a sphenoid wing meningioma, which is to our knowledge the largest mass-forming pachymeningitis published in the literature. Our second case depicts another presentation of extensive IgG4 pachymeningitis involving both cavernous sinuses and surrounding Meckel’s caves. The third case describes a patient with presumed lymphocytic hypophysitis, which was later determined to be IgG4-related hypophysitis with concomitant pachymeningitis and perineural spread along the optic nerves. The delayed diagnoses in our cases illustrates the diagnostic challenge that clinicians face in differentiating intracranial IgG4-RD from other infiltrative diseases such as sarcoidosis, granulomatous disease, tuberculosis and lymphoma. Earlier consideration of IgG4-related hypophysitis and hypertrophic pachymeningitis in the differential diagnosis can prevent significant morbidity including unnecessary surgical intervention and organ failure secondary to extensive fibrosis.

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Needle biopsy compared with surgical biopsy: pitfalls of small biopsy in histologial diagnosis of IgG4-related disease

Arthritis Research & Therapy ◽

10.1186/s13075-021-02432-y ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Yanying Liu ◽

Fei Yang ◽

Xiying Chi ◽

Yuxin Zhang ◽

Jiangnan Fu ◽

...

Keyword(s):

Needle Biopsy ◽

Plasma Cells ◽

Classification Criteria ◽

Histological Diagnosis ◽

Obliterative Phlebitis ◽

Surgical Biopsy ◽

Related Disease ◽

Igg4 Related Disease ◽

Significant Difference ◽

Storiform Fibrosis

Abstract Objective The growing utilization of needle biopsy has challenged the current pathology consensus of IgG4-related disease (IgG4-RD). The aims of this study were to identify the histological characteristics of needle biopsy and surgical specimens and evaluate the ability of needle biopsy in histological diagnosis of IgG4-RD. Methods Biopsies from patients who were referred to as IgG4-RD by the 2019 ACR/EULAR IgG4-RD classification criteria in Peking University People’s Hospital from 2012 to 2019 were re-evaluated. Typical histological features and diagnostic categories were compared between needle biopsy and surgical biopsy. Results In total, 69 patients met the 2019 ACR/EULAR classification criteria and 72 biopsies of them were re-evaluated. All cases showed lymphoplasmacytic infiltrate, while storiform fibrosis and obliterative phlebitis were only present in 35 (48.6%) and 23 (31.9%) specimens, respectively. Storiform fibrosis was more likely to be seen in retroperitoneum lesion (P = 0.033). Surgical biopsy showed significantly higher IgG4+ plasma cells/high-power field (IgG4/HPF) count (P < 0.01) and higher proportion of IgG4/HPF > 10 (P < 0.01). No significant difference was observed with regard to the ratio of IgG4+ plasma cells/IgG+ plasma cells (IgG4/IgG) (P = 0.399), storiform fibrosis (P = 0.739), and obliterative phletibis (P = 0.153). According to the 2011 comprehensive diagnostic criteria, patients who performed a needle biopsy were less likely to be probable IgG4-RD (P = 0.045). Based on the 2011 pathology consensus, needle biopsy was less likely to be diagnosed as IgG4-RD (P < 0.01), especially to be highly suggestive IgG4-RD (P < 0.01). Only 1/18 (5.6%) needle salivary specimens fulfilled the cutoff of IgG4/HPF > 100, which was significantly less than 15/23 (65.2%) of surgical ones (P < 0.01). Conclusions Needle biopsy shows an inferiority in detecting IgG4/HPF count but not in IgG4/IgG ratio, storiform fibrosis, and obliterative phlebitis. Compared with surgical samples, needle biopsy is less likely to obtain a histological diagnosis of IgG4-RD. A different IgG4/HPF threshold for needle biopsy of the salivary glands may be considered.

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Successful Management of Acquired Hemophilia A Associated with Bullous Pemphigoid: A Case Report and Review of the Literature

Case Reports in Hematology ◽

10.1155/2017/2057019 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Quentin Binet ◽

Catherine Lambert ◽

Laurine Sacré ◽

Stéphane Eeckhoudt ◽

Cedric Hermans

Keyword(s):

Bullous Pemphigoid ◽

Neutralizing Antibodies ◽

Hemophilia A ◽

Rare Condition ◽

Term Treatment ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Short Term Treatment ◽

Life Threatening ◽

Dose Levels

Background. Acquired hemophilia A (AHA) is a rare condition, due to the spontaneous formation of neutralizing antibodies against endogenous factor VIII. About half the cases are associated with pregnancy, postpartum, autoimmune diseases, malignancies, or adverse drug reactions. Symptoms include severe and unexpected bleeding that may prove life-threatening.Case Study. We report a case of AHA associated with bullous pemphigoid (BP), a chronic, autoimmune, subepidermal, blistering skin disease. To our knowledge, this is the 25th documented case of such an association. Following treatment for less than 3 months consisting of methylprednisolone at decreasing dose levels along with four courses of rituximab (monoclonal antibody directed against the CD20 protein), AHA was completely cured and BP well-controlled.Conclusions. This report illustrates a rare association of AHA and BP, supporting the possibility of eradicating the inhibitor with a well-conducted short-term treatment.

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