A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment?

The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies directed against factor VIII (FVIII) that occur in approximately 30% of people with severe hemophilia A. Emicizumab, an FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI.

Recombinant porcine factor VIII: Lessons from the past and place in the management of hemophilia A with inhibitors in 2021.

The most serious complication of factor VIII (FVIII) replacement therapy is the occurrence of anti-FVIII alloantibodies that can strongly reduce or abolish the effect of human FVIII products. Bypassing agents to control bleeding episodes are recommended for these patients, but their efficacy is difficult to predict and monitor. FVIII products derived from porcine plasma had an important role in the treatment of hemophilia A for 50 years, from 1954 to 2004. Indeed, porcine FVIII could achieve hemostasis in patients in whom human FVIII products were ineffective. A recombinant porcine FVIII product is now available. This highly purified protein has the same biochemical and hemostatic properties, but much lower risks of infection and toxicity compared with plasma-derived porcine FVIII. The product is licensed in the United States and Europe for the treatment of acquired hemophilia A. However, this recombinant molecule could also be of clinical interest for people with inherited hemophilia A and inhibitors, particularly for the management of bleeding episodes in people receiving emicizumab as prophylactic treatment in the absence of anti-porcine FVIII antibodies.

Hemofilia adquirida como manifestación inicial de recidiva de adenocarcinoma colorrectal / Acquired hemophilia as the initial manifestation of colorectal cancer's recurrence

Resumen Presentamos el caso de un varón de 86 años con un hematoma espontáneo en el músculo ilíaco izquierdo y diagnóstico previo de cáncer de colon en 1998 (estadio pT3N0M0), tratado quirúrgicamente mediante colectomía transversal, considerado en remisión completa. Tras realización de estudios complementarios se demostró la presencia de autoanticuerpos inhibidores del Factor VIII que confirmaron el diagnóstico de hemofilia adquirida. Durante el ingreso el paciente presentó un sangrado digestivo bajo que conllevó al descubrimiento de recidiva del adenocarcinoma colorrectal tratado previamente. Respondió de forma favorable a la terapia inicial con corticoides sistémicos y el complejo coagulante anti inhibidor que incluye el Factor VII activado [FEIBA].

Abstract We report the case of an 86-year-old man presenting with a spontaneous hematoma in the left iliac muscle and previous diagnosis of colon cancer in 1998 (stage pT3N0M0) treated with transverse colectomy and considered in complete remission. After a complete study, it was possible to identify the presence of Factor VIII inhibitors antibodies that confirmed the presence of acquired hemophilia. During hospitalization the patient presented a lower gastrointestinal bleeding leading to the diagnosis of recurrence of a previously treated colorectal adenocarcinoma. He responded to initial therapy with systemic corticoids and anti-inhibitory coagulant complex which includes activated VII Factor [FEIBA].

[Acquired hemophilia as the initial manifestation of colorectal cancer's recurrence]. / Hemofilia adquirida como manifestación inicial de recidiva de adenocarcinoma colorrectal.

We report the case of an 86-year-old man presenting with a spontaneous hematoma in the left iliac muscle and previous diagnosis of colon cancer in 1998 (stage pT3N0M0) treated with transverse colectomy and considered in complete remission. After a complete study, it was possible to identify the presence of Factor VIII inhibitors antibodies that confirmed the presence of acquired hemophilia. During hospitalization the patient presented a lower gastrointestinal bleeding leading to the diagnosis of recurrence of a previously treated colorectal adenocarcinoma. He responded to initial therapy with systemic corticoids and anti-inhibitory coagulant complex which includes activated VII Factor [FEIBA].

Presentamos el caso de un varón de 86 años con un hematoma espontáneo en el músculo ilíaco izquierdo y diagnóstico previo de cáncer de colon en 1998 (estadio pT3N0M0), tratado quirúrgicamente mediante colectomía transversal, considerado en remisión completa. Tras realización de estudios complementarios se demostró la presencia de autoanticuerpos inhibidores del Factor VIII que confirmaron el diagnóstico de hemofilia adquirida. Durante el ingreso el paciente presentó un sangrado digestivo bajo que conllevó al descubrimiento de recidiva del adenocarcinoma colorrectal tratado previamente. Respondió de forma favorable a la terapia inicial con corticoides sistémicos y el complejo coagulante anti inhibidor que incluye el Factor VII activado [FEIBA].

Lupus anticoagulant-hypoprothrombinemia syndrome and similar diseases: experiences at a single center in Japan.

Patients with lupus anticoagulant (LA), a thrombotic risk factor, along with decreased prothrombin (FII) activity are classified as lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) and occasionally show bleeding symptoms, although this is not essential for diagnosis. We treated 20 cases of LAHPS over a 3-year period. Median FII activity was 20.9% and the anti-prothrombin antibody (anti-II Ab), shown by ELISA findings, was detected in 55%. Bleeding symptoms were observed in 20%, although that finding was not correlated with FII activity or anti-FII Ab quantity. We also observed 21 LA cases with decreased activity of coagulation factors other than FII, which we have designated LAHPS-like syndrome (LLS). Among LLS patients, anti-FII Ab and bleeding symptoms were seen in 47.6% and 14.3%, respectively. Our findings suggest that bleeding in LAHPS and LLS cannot be explained only by FII activity decreased by anti-FII Ab. Low FVIII activity and the anti-FVIII antibody (anti-FVIII Ab) were detected in some LAHPS and LLS patients, making it difficult to distinguish those from acquired hemophilia A cases. Detection of anti-FVIII Ab quantity by ELISA may be useful for accurate determination, as that was not performed in our LAHPS or LLS patients.

Anti-factor VIII antibodies in brothers with haemophilia A share similar characteristics.

INTRODUCTION: The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is currently the most serious complication for patients with haemophilia A undergoing FVIII replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development. AIM: To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors. METHODS: The domain specificity of FVIII-specific IgG was analysed by antibody binding to FVIII fragments and homologue-scanning mutagenesis (HSM). The FVIII-specific IgG subclasses were measured by direct ELISA. RESULTS: Of the 16 patient analysed with both methods, 12 had A2- and 13 had C2-specific IgG. The presence of A1-, A3- or C1-specific IgG was identified in nine of 14 patients analysed by HSM. IgG1, IgG2 and IgG4 subclasses contributed to the anti-FVIII IgG response, and the amount of FVIII-specific IgG1 (r = 0.66) and IgG4 (r = 0.69) correlated significantly with inhibitor titres. Patients with high concentrations of total anti-FVIII IgG (r = 0.69) or high inhibitor titres (r = 0.52) had a high proportion of FVIII-specific IgG4. Statistical analysis revealed trends/evidence that the subclass distribution (P = 0.0847) and domain specificity to HC/LC (P = 0.0883) and A2/C2 (P = 0.0011) of anti-FVIII IgG were more similar in brothers compared to unrelated subjects. CONCLUSION: Overall, our data provide a first hint that anti-FVIII IgG characteristics are comparable among haemophilic brothers with inhibitors. Whether genetic factors also influence the nature of patients' antibodies needs to be confirmed in a larger study population.

[Acquired A hemophilia and lymphoproliferative diseases: A literature review]. / Hémophilie A acquise et hémopathies lymphoïdes: revue de la littérature.

Acquired A haemophilia is a rare but severe autoimmune disease. It is caused by autoantibodies against the coagulation factor VIII. These autoantibodies could have different consequences: no effect, inhibition of factor VIII or factor VIII activity hydrolyzing. In about half of the cases, no cause is associated with the disorder [idiopathic acquired A haemophilia]. But in remaining 50% of the patients, some circumstances could be associated with acquired hemophilia: post-partum, autoimmune disorders, cancer and sometimes malignant blood disorders. The objective of this article was to review the literature about acquired A hemophilia associated with lymphoproliferative diseases.

Efecto del inhibidor lúpico o anti-factor VIII sobre la actividad del factor VIII-sustrato cromogénico / Lupus anticoagulant or anti-factor VIII effect on factor VIII activity-chromogenic substrate

El objetivo del trabajo fue analizar el efecto de inmunoglobulinas (IgG) purificadas con actividad anti-factor VIII neutralizante o inhibidor lúpico, sobre el factor VIII medido por sustrato cromogénico (factor VIII SC), con el propósito de validar el método para detectar anti-factor VIII en presencia de inhibidor lúpico. Se aisló la fracción IgG (cromatografía de afinidad) a partir de plasmas normales (IgG-N), con anti-factor VIII (IgG-aFVIII) o con inhibidor lúpico (IgG-IL), preparándose un pool normal como aporte de factor VIII en los ensayos de inhibición. Se analizaron las mezclas del pool normal con IgG-N, IgG-aFVIII, IgG-IL o la combinación de IgG-aFVIII+IgG-IL, inmediatamente y luego de 2 h a 37 ºC, determinándose la actividad del factor VIII SC y el índice de inhibición inmediato (Ii) o post-incubación (Ip). La inhibición y la potenciación producida por IgG-aFVIII+IgG-IL (Ii:30%±0,7; Ip:55%±2,7), fueron similares a las observadas con IgG-aFVIII sola (Ii:30%±0,6; Ip:55%±2,7). La IgG-IL no afectó la actividad de factor VIII SC. Semejante a lo observado en plasma, la IgG-IL no interfirió en la inhibición del factor VIII SC mediada por IgG-aFVIII. Se confirmó así la especificidad del método amidolítico, que permite detectar inhibidores anti-factor VIII independientemente de la coexistencia con el inhibidor lúpico, solucionando el problema diagnóstico planteado en hemofilia A.

To analyse the effect of purified immunoglobulins (IgG) with anti-factor VIII or lupus anticoagulant activity on factor VIII measured by chromogenic substrate (factor VIIICS), in order to validate the chromogenic substrate method for detection of anti-factor VIII activity in the presence of lupus anticoagulant. IgG fractions were purified (affinity chromatography) from normal plasmas (IgG-N) and plasmas with anti-factor VIII (IgG-aFVIII) or lupus anticoagulant (IgG-LA). A normal plasma pool was prepared as source of factor VIII in the inhibition tests. Mixtures of this pool with IgG-N, IgG-aFVIII, IgG-LA or IgG-aFVIII+IgG-LA were tested immediately or after 2 h at 37 °C by factor VIIICS method; inhibition index (Ii) and post-incubation index (Ip) were calculated. The inhibitory and progressive inhibitory effects produced by IgG-aFVIII+IgG-LA (Ii:30%±0.7; Ip:55%±2.7) were similar to those observed with IgG-aFVIII (Ii:30%±0.6; Ip:55%±2.7). The IgG-LA did not inhibit the factor VIIIcs activity. As was observed in plasma samples, IgG-aFVIII and the mixture of IgG-aFVIII+IgG-LA inhibited factor VIIICS, whereas IgG-LA did not. These results confirm the specificity of the amidolytic method in detecting anti-factor VIII inhibitors independently of the presence of lupus anticoagulant, thus solving the diagnostic problem in haemophilia A.

Detection and IgG subclass analysis of antibodies to factor VIII in multitransfused haemophiliacs and healthy individuals.

Using a binding assay to immobilized factor VIII (F VIII) (ELISA) we measured the amount of IgG with binding capacity to FVIII, in the plasma of patients with an inhibitor to F VIII, in multitransfused haemophiliacs without inhibitor and in a control group of blood donors. It was shown that the amount of IgG bound to VIII was elevated in patients with an inhibitor although a weak correlation could be established between the inhibitor titre (BU) and the amount of bound IgG. In all haemophiliacs without inhibitor, IgG bound to F VIII were present. Although the mean value of IgG bound to F VIII was significantly lower than the amount detected in patients with F VIII inhibitors, a group of patients developed an equal amount of IgG recognizing the F VIII molecules to the amount of IgG measured in inhibitor patients. These results indicate that the presence of an inhibitor is not related to the amount of specific IgG bound to F VIII but more likely to the position of epitopes recognized by specific IgG. The presence of IgG bound to F VIII was detected in 92% of control blood donors and an inhibitor to F VIII ranging from 0.5 to 1.3 BU mL(-1) in 17% of them. The isotypes of bound immunoglobins were identified in patients and controls: IgG4 subclass was predominant only in patients with an inhibitor and usually associated with antibodies of one or more of the other subclasses. In noninhibitor patients, very few had antibodies of IgG4 subclass with binding capacity to F VIII. These results raised the question of the clinical significance of these antibodies in multitransfused patients. The study indicates that binding assay is a complementary test to be used in multitransfused patients but cannot be used instead of the coagulation tests for detection of inhibitors.