Acquired hemophilia A associated with Epstein-Barr-virus-associated T/natural killer-cell lymphoproliferative disease: A case report.

INTRODUCTION: Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Hematological malignancies, especially lymphoid malignancies, are known to be underlying causes of AHA; however, thus far, there is no report of AHA associated with Epstein-Barr-virus-associated T/natural killer-cell lymphoproliferative disease (EBV-T/NK-LPD). Here, we present a case of AHA that developed during treatment for EBV-T/NK-LPD. HISTORY: A 69-year-old man visited our hospital because of general fatigue. Blood examination showed pancytopenia, and computed tomography revealed whole-body lymphadenopathy, but there were no findings indicating hematological malignancy from bone marrow aspiration and cervical lymph node biopsy. The level of EBV DNA in peripheral blood was extremely high, and he was diagnosed with EBV-T/NK-LPD. EBV-T/NK-LPD improved with prednisolone (PSL) administration. Seventeen months after starting treatment, the patient complained of back and right leg pain. At that time, he had been treated with low-dose PSL, and EBV-T/NK-LPD was well controlled. Imaging revealed hematoma of the right iliopsoas muscle. Prolonged activated partial thromboplastin time (APTT) was the only abnormal finding in a screening coagulation test. FVIII coagulant activity was below detection limit, and FVIII inhibitor level was increased. From these results, he was diagnosed with AHA.A higher dose of PSL was administered, and, after 1 month of treatment, FVIII activity gradually increased, and FVIII inhibitor level became undetectable. APTT also normalized, and complete remission was achieved and maintained for 13 months with low-dose PSL. During treatment, EBV-T/NK-LPD was well controlled. CONCLUSION: It is speculated that proliferating lymphocytes interfere with normal immune functions and that abnormal autoantibodies are produced from those lymphocytes in patients with LPD. Therefore, we speculate that EBV-infected and proliferating monoclonal NK cells might have modulated the immune system and produced autoantibodies against FVIII, thus causing AHA in this patient with EBV-T/NK-LPD.

HIV-associated and idiopathic-acquired haemophilia A: A single-centre case series from Cape Town, South Africa.

Acquired haemophilia A is a rare coagulation disorder, which can lead to life-threatening haemorrhages if not identified and treated promptly. It is characterised by the presence of autoantibodies (inhibitors) to factor VIII. Acquired haemophilia A associated with HIV is a rare but well described phenomenon with limited directions to its management. We comparatively describe four patients - two with HIV and two without - that presented with unusual bleeding episodes with a prolonged activated partial thromboplastin time secondary to factor VIII inhibitors. An empiric observation is that the patients with acquired haemophilia A associated with HIV had higher antibody titres at presentation, that required more prolonged immunosuppressive therapy to induce remission.

Micro-elimination of HCV as a possible therapeutic strategy: our experience and a review of literature.

BACKGROUND: Serbia has an intermediate estimated prevalence of chronic hepatitis C (CHC) infection, approximately 1.13%, with hepatitis C remaining one of the leading causes of liver-related morbidity and mortality in Serbia with impaired quality of life and overwhelming cost of treating its complications As the availability of new treatment options and resources for screening remains limited, micro-elimination of CHC becomes a top priority. METHODS: Review of the available published data related to the clinical and epidemiological situation of the hepatitis C infection in Serbia, including the unpublished data from the databases of four major reference centres in Serbia (Clinical Center Serbia, Clinical Center Nis, Clinical Center Vojvodina and Clinical Center Kragujevac). RESULTS: Currently in Serbia, micro-elimination appears to be realistic in the patients with haemophilia, who represent a small, well-defined subpopulation, under constant monitoring by the healthcare system. Other feasible targets for micro-elimination of CHC infection in Serbia are patients on hemodialysis, prisoners and people who inject drugs. CONCLUSIONS: Micro-elimination is feasible in Serbia, especially in the subpopulation of patients with haemophilia. This may represent an initial step towards achieving the WHO objective to eliminate hepatitis C infection by 2030.

Impact of Blood Transfusion on the Prevalence of HHpgV-1, HPgV-1, and B19V Among Iranian HCV-infected Patients With Hemophilia.

OBJECTIVE: Blood-derived products from patient with hemophilia treated by factor VIII concentrates are potential sources of transfusion-transmitted infections, including human immunodeficiency virus, hepatitis, human pegivirus-1 (HPgV-1), B19 virus, and also human hepegivirus-1 (HHpgV-1). In the current study, we investigated the impact of blood transfusion on the prevalence of HHpgV-1, HPgV-1, and B19 virus in plasma of Iranian patient with hemophilia after direct-acting antiviral treatment of hepatitis C virus (HCV) infections for the first time. MATERIALS AND METHODS: A total of 170 patients with hemophilia who received direct-acting antivirals were enrolled in this study. Among them, 92 patients had a history of blood transfusion. The presence of HHpgV-1, HPgV-1, and B19 virus was detected by nested polymerase chain reaction analysis using the conserved primers. The plasmids harboring 5'-UTR and NS3 were used as positive controls for HPgV-1 and HHpgV-1, respectively. RESULTS: Our data identified 3 individuals with HHpgV-1 viremia (1.76%), 11 individuals with HPgV-1 viremia (6.47%), and 33 individuals with B19 viremia (19.4%). All patients were negative for hepatitis B virus, human immunodeficiency virus, and HCV infections. These findings indicated lower transmissibility or higher rates of virus clearance for HHpgV-1, HPgV-1, and B19 virus as compared with other bloodborne human flaviviruses such as HCV. However, the prevalence of B19 virus was significantly higher than the other 2 viruses. CONCLUSION: In general, these findings showed that the history of blood transfusion could increase the risk of viral transmission of bloodborne viruses among patient with hemophilia.

Current trends of Hepatitis C virus genotypes and associated risk factors in hemophilia patients in Pakistan.

Hemophilia is a rare bleeding disorder that needs plasma or clotting factor concentrate transfusion. Therefore chances of blood-borne pathogens like HCV transmission increase due to high prevalence in healthy donors. This study was aimed to determine the prevalence of HCV genotypes and associated risk factors in hemophilia patients of Khyber Pakhtunkhwa, Pakistan. Blood samples and data were collected from 672 hemophiliacs after proper consent obtained from each patient. Samples were analyzed for anti-HCV, HCV RNA and HCV genotype/s detection. Of the total, 22.32% (150) were anti-HCV positive, of which HCV RNA was detected in 18.45% (124) individuals. HCV genotype 3a was found with significantly higher prevalence (p<0.05) (19.35%) as compared to 2a (16.13%) and 1a (12.90%). HCV-3b and HCV-4 were found each in 3.22% samples. Dual infection of genotypes was found in 22.58% of individuals and 22.58% HCV RNA positive sampels were not typed. A total of 572 (85.12%) subjects had hemophilia A and 100 (14.88%) had hemophilia B. In hemophiliacs A the most dominant genotype was 3a (19.27%) while in hemophilia B, genotype 1a was prevalent (26.67%). Whole blood and plasma transfusion were observed as the main risk factors of HCV. It is concluded that HCV genotype 3a and 2a are prevalent in hemophilia patients of Khyber Pakhtunkhwa Pakistan and the main risk factor observed was an unscreened whole blood transfusion.

New data from the Italian National Register of Congenital Coagulopathies, 2016 Annual Survey.

BACKGROUND: In Italy, the National Register of Congenital Coagulopathies (NRCC) collects epidemiological and therapeutic data from patients affected by haemophilia A (HA), haemophilia B (HB), von Willebrand's disease (vWD) and other rare coagulation disorders. Here we present data from the 2016 annual survey. MATERIALS AND METHODS: Data are provided by the Italian Haemophilia Centres, on a voluntary basis. Information flows from every Centre to a web-based platform of the Italian Association of Haemophilia Centres, shared with the Italian National Institute of Health, in accordance with current privacy laws. Patients are classified by diagnosis, disease severity, age, gender and treatment-related complications. RESULTS: In 2016, the total number of patients with congenital coagulopathies in the NRCC was 10,360: 39.8% of these patients had HA, 31.5% had vWD, 8.5% had HB, and 20.2% had less common factor deficiencies. The overall prevalence of HA and HB was 13.9/100,000 males and 3.0/100,000 males, respectively. The overall prevalence of vWD was 5.4/100,000 inhabitants. During 2016, 126 patients had current alloantibodies to factor VIII (FVIII) or factor IX (FIX) and were under treatment with bypassing agents and/or immune tolerance induction. Overall, 388 patients with a history of alloantibodies were recorded in the NRCC of whom 337 with severe HA and 12 with severe HB. Coagulation factor use, evaluated from treatment plans, was approximately 451,000,000 IU of FVIII for HA patients (7.5 IU/inhabitant), and approximately 53,000,000 IU of FIX for HB patients (0.9 IU/inhabitant). DISCUSSION: The prevalences of HA and HB fall within the ranges reported in more developed countries; the consumption of FVIII and FIX was in line with that of other European countries (France, United Kingdom) and Canada. The NRCC, with its bleeding disorder dataset, is a helpful tool for shaping public health policies, as well as planning clinical and epidemiological research projects.

Occult hepatitis C virus infection in hemophilia patients and its correlation with interferon lambda 3 and 4 polymorphisms.

Occult HCV infection (OCI) is described as the presence of HCV RNA in the liver and peripheral blood mononuclear cells (PBMCs), with no HCV RNA in the serum. Single-nucleotide polymorphisms (SNPs) near interferon lambda 3/4 (IFNL3/4) gene are associated with spontaneous clearance and treatment response in patients with hepatitis C virus (HCV) infection. In this study, we evaluated the frequency of OCI in hemophilia patients and determined the association of three IFNL3 SNPs (rs12979860, rs12980275, and rs8099917) and IFNL4 ss469415590 with OCI positivity. A total of 450 hemophilia patients with HCV negative markers were included in this study. Positive- and negative-stranded HCV-RNA was determined in peripheral blood mononuclear cells (PBMCs) samples by reverse-transcription polymerase chain reaction (RT-PCR) method. IFNL3 SNPs and IFNL4 ss469415590 were genotyped by PCR-RFLP and TaqMan® Real-Time PCR methods, respectively. The frequency of OCI was estimated at 10.2%. Among 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. Compared to patients without OCI, unfavorable IFNL3 rs12979860 TT, IFNL3 rs8099917 GG, IFNL3 rs12980275 GG, and IFNL4 ss469415590 ∆G/∆G genotypes were more frequently reported in OCI patients. The multivariate logistic regression analysis showed that alanine aminotransferase (ALT), cholesterol, triglyceride, IFNL3 rs12979860 (TT), IFNL3 rs8099917 (GG), IFNL3 rs12980275 (GG), and IFNL4 ss469415590 (∆G/∆G) were associated with OCI positivity. In conclusion, we studied the incidence of OCI in Iranian patients with hemophilia for the first time. Our results demonstrated that unfavorable genotypes of IFNL3 SNPs and IFNL4 ss469415590 have a strong relationship with OCI positivity. It seems that the host immune response plays a vital role in OCI positivity.

Elimination of hepatitis C virus infection in patients with haemophilia in Belgium: A single-centre experience.

INTRODUCTION: Patients with haemophilia are one of the subgroups with a high prevalence of hepatitis C virus (HCV) infection. They are a potential target group to eliminate HCV infection thanks to the availability of direct-acting antiviral (DAA) therapy. AIM: To investigate the results of DAA therapy in a cohort of patients with bleeding disorders. METHODS: This retrospective study was conducted between July 2018 and April 2019. All patients born before 1990 with haemophilia, von Willebrand factor Disease, factor V deficiency, factor VII deficiency or afibrinogenemia were included in this study. RESULTS: Of 299 patients, 297 (99.3%) were tested for HCV antibody presence and 211 (71.0%) were positive. Of these, 205 (97.1%) were tested for HCV RNA and 153 (72.1%) were chronically infected. In total, 127 (83.0%) received antiviral therapy, and 110 (71.8%) patients were cured by antiviral treatment. The presence of cirrhosis was significantly higher in patients without a cure for HCV infection when compared to patients who achieved sustained virologic response by treatment or never infected (32.6% vs. 12.8% vs. 0%; P < .001). At the end of follow-up in 2019, only 14 (9.1%) patients had a remaining HCV infection. Ten (71.4%) were lost to follow-up, one (7.1%) patient refused, two (14.2%) had comorbidities and one (7.1%) will start treatment soon. CONCLUSION: In this cohort, the elimination targets for HCV infection in 2030 as proposed by the World Health Organization were already reached. Nevertheless, in order to cure every patient, monitoring tools are necessary.

Antiviral therapy for HCV in hemophilia A patients with HIV-1 co-infection.

Anti-hepatitis C virus (HCV) treatment for human immunodeficiency virus (HIV)/HCV co-positive patients with hemophilia A presents numerous problems in terms of safety and effectiveness. The emergence of direct-acting antiviral (DAA) regimens has led to tremendous changes in the management of HIV/HCV co-infection over the past few years, but the application of DAA in patients with hemophilia complicated with HIV/HCV co-infection has rarely been reported.We retrospectively analyzed the clinical course and outcome of hemophilia A patients with HIV/HCV co-infection receiving DAA with a focus on the virological response, changes in cluster of differentiation 4 lymphocyte (CD4) count, side effects, and impact on bleeding before and after DAA therapy.A total of 12 hemophilia A patients with HIV/HCV co-infection were included, 9 of which were severe. All the patients were in stable states with CD4 counts >200/mm and plasma HIV ribonucleic acid (RNA) suppressed (<40 IU/mL) while taking the antiretroviral regimen. Majority of the patients (n = 9, 75.0%) were infected with HCV genotype (GT) 1b, while 2 and 1 was infected with HCV GT 2i and HCV GT 3, respectively.After 12 weeks of DAA treatment, 11 patients (91.7%) obtained sustained virologic response within 24 weeks of discontinuation of treatment (SVR24), except 1 patient who was treated with sofosbuvir (SOF) + pegylated interferon + ribavirin (PR), which was then switched to daclatasvir (DCV) + asunaprevir (ASV) for 12 weeks; this patient then achieved SVR24. During DAA treatment, HIV RNA in all the patients was constantly suppressed, while CD4 counts showed no obvious change.The most common treatment-emergent adverse events were weakness and loss of appetite (generally mild). There was no evidence of an increased tendency of bleeding, and changes in response to replacement.DAA therapy offered a safe and well-tolerated management strategy for HIV/HCV co-infected patients with hemophilia A. An awareness of the potential drug-drug interactions (DDI) between DAA and combination antiretroviral therapy (cART) by clinicians is important for optimal management of co-infected patients.

First Report of Prevalence of Blood-Borne Viruses (HBV, HCV, HIV, HTLV-1 and Parvovirus B19) Among Hemophilia Patients in Afghanistan.

Blood-borne viruses including Hepatitis B and C, HIV, HTLV-1 and parvovirus B19 are still a factor of concern, especially for hemophilia patients. Although the safety of the blood supply continues to improve worldwide, the blood supply system in Afghanistan was damaged by many years of conflict and political instability. To date, there are few studies focused on the prevalence of blood-borne viruses in hemophilia patients. This study is first to investigate the prevalence of five blood-borne viruses in Afghanistan hemophilia patients in four cities including Kabul, Herat, Mazar-i-Sharif and Jalal Abad. A total of 80 hemophilia male patients were screening for the presence of five transfusion-transmitted viruses using ELISA and PCR. Data obtained showed 2.5% seropositivity for HBV, 8.75% seropositivity for HCV, and 91.25% seropositivity for parvovirus B19. None of the patients were positive for HIV and HTLV-1 and the prevalence of HCV was higher in older patients rather than younger patients. This finding, the first to report in Afghanistan, shows a high prevalence of parvovirus B19 in Afghanistan hemophilia patients and implementation of highly sensitive screening is necessary.

Interferon-free therapy with direct acting antivirals for HCV/HIV-1 co-infected Japanese patients with inherited bleeding disorders.

INTRODUCTION: Almost 30 years ago, about 30% of Japanese hemophiliacs became infected with HIV-1 and hepatitis C virus (HCV) after receiving contaminated blood products. While several studies have reported the high efficacy and safety of direct acting antivirals (DAA) in HIV-1 co-infected patients, such data are limited in hemophiliacs. METHODS: We conducted a single-center, open-label study involving 27 Japanese patients (median age; 45 years) with inherited bleeding disorders who were co-infected with HCV/HIV-1. Patients with HCV genotype 1 (GT1) and GT4 received ledipasvir (90 mg) plus sofosbuvir (400 mg), those with HCV GT2 received sofosbuvir plus weight-based ribavirin, and those with HCV GT3 received daclatasvir (60 mg) plus sofosbuvir. Treatment was continued for 12 weeks in all patients. The primary endpoints were rate of sustained virologic response at 12 weeks after end of therapy (SVR12) and occurrence of adverse events during DAA therapy. RESULTS: Eighteen (67%) patients had had received interferon-based therapy, and 11 (41%) had compensated cirrhosis. HCV genotypes were GT1a 4 (15%), GT1b 16 (59%), GT1 undetermined 2 (7%), GT2a 1 (4%), GT3a 3 (11%) and GT4a 1 (4%). All patients were on combination antiretroviral therapy (cART) and had undetectable HIV-1 viral load (<20 copies/µL) at baseline. All patients achieved SVR12. Serious adverse events were observed in 3 patients: arteritis of the leg, which resolved after completion of DAA therapy, asymptomatic QT prolongation and gastrointestinal hemorrhage. cART failure was noted in one patient due to emergence of raltegravir resistance during ledipasvir/sofosbuvir treatment. Although α-fetoprotein, Mac-2 binding protein glycosylation isomer (M2BPGi), and Fibro Scan (FS) scores decreased in most patients during DAA therapy, M2BPGi (>2.0 cutoff index) and FS scores (>15.0 kPa) were still high in 6 patients at week 36. CONCLUSIONS: DAA therapy is effective in all patients. However, adverse events and efficacy of cART should be monitored closely.

Direct Acting Antiviral Agents in Korean Patients with Chronic Hepatitis C and Hemophilia Who Are Treatment-Naïve or Treatment-Experienced.

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. METHODS: Patients (n=30) were enrolled between September 2015 and April 2016. Twenty-six patients were genotype 1 (1b, n=21; 1a, n=5) and four patients were genotype 2a/2b. Among 21 patients with genotype 1b, Y93H resistance-associated variants (RAVs) were detected in three patients (14.3%). We evaluated sustained virologic response (SVRs) at 12 weeks, as well as relapse and safety. RESULTS: Five patients with genotype 1a and three patients with genotype 1b (RAV positive) received ledipasvir/sofosbuvir for 12 weeks. SVR12 rate was 100% (8/8). Eleven patients with genotype 1b were treatment-naïve and received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 91% (10/11). One patient experienced viral breakthrough without RAV at 12 weeks. Seven treatment-experienced patients with genotype 1b received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 85.7% (6/7). One patient experienced viral breakthrough with RAV (L31M, Y93H) at 12 weeks. Four patients with genotype 2a/2b received sofosbuvir plus ribavirin for 12 weeks. SVR12 rate was 100% (4/4). No serious adverse event-related discontinuations were noted. CONCLUSIONS: New direct acting antiviral treatment achieved high SVRs rates at 12 weeks in CHC patients with hemophilia without serious adverse events.

Evaluation of Viremia Frequencies of a Novel Human Pegivirus by Using Bioinformatic Screening and PCR.

Next-generation sequencing has critical applications in virus discovery, diagnostics, and environmental surveillance. We used metagenomic sequence libraries for retrospective screening of plasma samples for the recently discovered human hepegivirus 1 (HHpgV-1). From a cohort of 150 hepatitis C virus (HCV)-positive case-patients, we identified 2 persons with HHpgV-1 viremia and a high frequency of human pegivirus (HPgV) viremia (14%). Detection of HHpgV-1 and HPgV was concordant with parallel PCR-based screening using conserved primers matching groups 1 (HPgV) and 2 (HHPgV-1) nonstructural 3 region sequences. PCR identified 1 HHPgV-1-positive person with viremia from a group of 195 persons with hemophilia who had been exposed to nonvirally inactivated factor VII/IX; 18 (9%) were HPgV-positive. Relative to HCV and HPgV, active infections with HHpgV-1 were infrequently detected in blood, even in groups that had substantial parenteral exposure. Our findings are consistent with lower transmissibility or higher rates of virus clearance for HHpgV-1 than for other bloodborne human flaviviruses.

Long-term follow up of HIV-1-infected Korean haemophiliacs, after infection from a common source of virus.

In the early 1990s, 20 haemophiliacs (HPs) were infected with a common source of HIV-1 viruses through the contaminated clotting factor IX. The aim of this study is to review 20 HPs infected with a common source of virus. The enrolled patients have been consecutively treated with Korean red ginseng (KRG), zidovudine (ZDV) or two-drug therapy and highly active antiretroviral therapy (HAART). We determined full-length pol gene over 20 years and human leukocyte antigen (HLA) class I with peripheral blood mononuclear cells and reviewed medical records. Eighteen HPs experienced various opportunistic infections or clinical manifestations. There were significant inverse correlations between the HLA prognostic score and the annual decrease in CD4+ T-cell counts prior to HAART (AD) (P < 0.05) and the amount of KRG and the AD (P < 0.01). From 1998, the HPs had been treated with HAART. Each of the two patients died without and with HAART regimen respectively. At present, 16 HPs have been alive with HAART. Among the 16 HPs, 12 and 4 are on HAART-plus-KRG and HAART only respectively. Eleven HPs including 2 HPs with G-to-A hypermutations had revealed resistance mutations. Ten and two HPs have shown poor adherence and incomplete viral suppres-sion on HAART respectively. Virological failure based on WHO guidelines was not observed on KRG-plus-HAART. Two HPs revealed additional resistance mutations against two classes on KRG-plus-HAART. As a nationwide study, we first report overall features on clinical course of Korean haemophiliacs. Further education on the importance of drug adherence is needed.

Acquired hemophilia A in the HIV-infected patient: a case report and literature review.

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Spontaneous bleeding in the various sites and severity is the most common clinical presentation. Here, we report a 74-year-old Thai woman with HIV infection who presented with spontaneous ecchymoses. The laboratory revealed isolated activated partial thromboplastin time prolongation with low FVIII activity and a presence of FVIII inhibitor. She was diagnosed with acquired hemophilia A. Corticosteroid monotherapy was the treatment regimen for inhibitor eradication. We demonstrate the clinical course of the rare condition and review the relevant literature.

Selection of TI8-8V mutant associated with long-term control of HIV-1 by cross-reactive HLA-B*51:01-restricted cytotoxic T cells.

Elite controllers of HIV-1-infected HLA-B*51:01(+) hemophiliacs, who remain disease free and have a very low plasma viral load for >30 y, had the 8V mutation at an immunodominant Pol283-8 (TI8) epitope, whereas the 8T mutant was predominantly selected in other HIV-1-infected HLA-B*51:01(+) hemophiliacs, suggesting an important role of the 8V mutant selection in long-term control of HIV-1. However, the mechanism of this selection and the long-term control in these elite controllers remains unknown. In this study, we investigated the mechanism of the 8V mutant selection in these controllers. TI8-specific CTLs from these individuals evenly recognized both TI8 peptide-pulsed and TI8-8V peptide-pulsed cells and effectively suppressed replication of wild-type (WT) and the 8V viruses. However, the results of a competitive viral suppression assay demonstrated that CTLs from the individual who had WT virus could discriminate WT virus from the 8V virus, whereas those from the individuals who had the 8V virus evenly recognized both viruses. The former CTLs carried TCRs with weaker affinity for the HLA-B*51:01-TI8-8V molecule than for the HLA-B*51:01-TI-8 one, whereas the latter ones carried TCRs with similar affinity for both molecules. The reconstruction of the TCRs from these CTLs in TCR-deficient cells confirmed the different recognition of the TCRs for these epitopes. The present study showed that the 8V mutant virus could be selected by cross-reactive CTLs carrying TCR that could discriminate a small difference between the two molecules. The selection of the 8V mutant and elicitation of these two cross-reactive CTLs may contribute to the long-term control of HIV-1.

[The IgG subclasses in patients with inhibitory form of hemophilia infected and noninfected with viruses].

The sample consisted of 102 patients with hemophilia infected and non-infected with hepatitis viruses. It is established that in case of inhibitory form of hemophilia concentration of IgG increases at the expense of subclass II and in case of non-inhibitory form of hemophilia valuable increase of concentration of IgG occurs at the expense of subclasses I, II and III under concomitant chronic hepatitis. No significant differences between these groups in levels of antibodies to factors VIII and IX is established.