A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

Haemophilia registry of the Medical Committee of the Swiss Hemophilia Society. Update and annual survey 2010-2011.

The Haemophilia Registry of the Swiss Haemophilia Society was created in the year 2000. The latest records from October 31st 2011 are presented here. Included are all patients with haemophilia A or B and other inherited coagulation disorders (including VWD patients with R-Co activity below 10%) known and followed by the 11 paediatric and 12 adult haemophilia treatment or reference centers. Currently there are 950 patients registered, the majority of which (585) having haemophilia A. Disease severity is graded according to ISTH criteria and its distribution between mild, moderate and severe haemophilia is similar to data from other European and American registries. The majority (about two thirds) of Swiss patients with haemophilia A or B are treated on-demand, with only about 20% of patients being on prophylaxis. The figure is different in paediatrics and young adults (1st and 2nd decades), where 80 to 90% of patients with haemophilia A are under regular prophylaxis. Interestingly enough, use of factor concentrates, although readily available, is rather low in Switzerland, especially when taking the country's GDP into account: The total amount of factor VIII and IX was 4.94 U pro capita, comparable to other European countries with distinctly lower incomes (Poland, Slovakia, Hungary). This finding is mainly due to the afore mentioned low rate of prophylactic treatment of haemophilia in our country. Our registry remains an important instrument of quality control of haemophilia therapy in Switzerland.

Hemophilia Registry of the Medical Committee of the Swiss Hemophilia Society: Update and Annual Survey 2008.

The Swiss Haemophilia Registry of the Medical Committee of the Swiss Haemophilia Society was established in 2000. Primarily it bears epidemiological and basic clinical data (incidence, type and severity of the disease, age groups, centres, mortality). Two thirds of the questions of the WFH Global Survey can be answered, especially those concerning use of concentrates (global, per capita) and treatment modalities (on-demand versus prophylactic regimens). Moreover, the registry is an important tool for quality control of the haemophilia treatment centres. There are no informations about infectious diseases like hepatitis or HIV, due to non-anonymisation of the data. We plan to incorporate the results of the mutation analysis in the future.

High number of CD56(bright) NK-cells and persistently low CD4+ T-cells in a hemophiliac HIV/HCV co-infected patient without opportunistic infections.

BACKGROUND: Both the human immunodeficiency virus (HIV) and hepatitis C virus (HCV), either alone or as coinfections, persist in their hosts by destroying and/or escaping immune defenses, with high morbidity as consequence. In some cases, however, a balance between infection and immunity is reached, leading to prolonged asymptomatic periods. We report a case of such an indolent co-infection, which could be explained by the development of a peculiar subset of Natural Killer (NK) cells. RESULTS: Persistently high peripheral levels of CD56+ NK cells were observed in a peculiar hemophiliac HIV/HCV co-infected patient with low CD4 counts, almost undetectable HIV viral load and no opportunistic infections. Thorough analysis of NK-subsets allowed to identify a marked increase in the CD56bright/dim cell ratio and low numbers of CD16+/CD56- cells. These cells have high levels of natural cytotoxicity receptors but low NCR2 and CD69, and lack both CD57 and CD25 expression. The degranulation potential of NK-cells which correlates with target cytolysis was atypically mainly performed by CD56bright NK-cells, whereas no production of interferon γ (IFN-γ) was observed following NK activation by K562 cells. CONCLUSIONS: These data suggest that the expansion and lytic capacity of the CD56bright NK subset may be involved in the protection of this « rare » HIV/HCV co-infected hemophiliac A patient from opportunistic infections and virus-related cancers despite very low CD4+ cell counts.

Unexpected bleeding following eyelid tumor resection leading to the rare diagnosis of acquired haemophilia.

BACKGROUND: Our goal is to report for the first time in the literature a case of uncontrolled bleeding after an oculoplastic surgical procedure leading to the diagnosis of acquired haemophilia. HISTORY AND SIGNS: An 82-year-old patient underwent tumor excision and reconstruction of his right lower eyelid. On the same day, uncontrolled bleeding occurred that resisted optimal blood pressure control, external compression, surgical haemostasis and wound revision. Usual coagulation screening tests were normal, except for a slightly prolonged activated partial thromboplastin time. THERAPY AND OUTCOME: Extensive coagulation check was performed, which showed a severely reduced factor VIII due to the presence of an inhibitor. The bleeding was immediately stopped after administration of recombinant factor VIIa. After healing of the wound, factor VIIa treatment was replaced by immunosuppressive therapy. The factor VIII inhibitor became unmeasurable and remained so for three months after stopping the immunosuppressive therapy. CONCLUSIONS: Ophthalmologists confronted with unexpected uncontrolled bleeding should think about the possibility of blood dyscrasia, in particular acquired haemophilia.

Pharmacovigilance [Pharmacovigilance update].

The main pharmacovigilance updates in 2014 are reviewed. Ivabradine: increased risk of cardiovascular death and myocardial infarction in patients with symptomatic angina treated with high dosages. Clopidogrel: rare observations of acquired hemophilia. Orlistat: may reduce the absorption of HIV antiretrovirals. Ponatinib: increased risk of arteriopathy and thrombosis. Axitinib: significant risk of heart failure (class effect). Tocilizumab: possible causal relationship with the emergence or aggravation of psoriasis. Lithium: hypercalcemia and hyperparathyroidism commonly observed. Sildenalfil: suspected causal association with melanoma, so far not proven, Methylphenidate: rare observations of priapism. St John's wort (Hypericum): reduced effectiveness of hormonal contraceptives, including implants.