Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate

The incidence of neutralizing isoantibody formation to infused factor VIII in a cohort of 67 hemophilia A patients, born between January 1, 1971 and April 30, 1990, who had been treated exclusively with lyophilized cryoprecipitate, was 6% (5.3 per 1,000 patient years of observation). The age-dependent cumulative risk was 4.6% at 4 years of age and 6.7% at 8 years of age. Recent reports in patients treated with a variety of more pure concentrates show a much higher incidence of inhibitor formation and tend to be used as a reference when new concentrates are introduced. We believe that a patient group, such as the one studied here, is a more suitable reference population because these patients have been exclusively treated with a single factor VIII preparation.     

Lymphadenopathy-associated virus antibodies and T cells in hemophiliacs treated with cryoprecipitate or concentrate

Evidence for exposure to lymphadenopathy-associated virus (LAV) was investigated in 48 patients with hemophilia, 15 of whom had been treated exclusively with single-donor cryoprecipitate. The prevalence of antibodies to LAV in all patients was 53% in 1983 and 63% in 1984, while in patients treated only with cryoprecipitate, the prevalence was 31% in 1983 and 40% in 1984. Patients treated with any concentrate had a seroprevalence of 65% in 1983 and 77% in 1984. Seropositive patients were more likely to have a significant reduction in the ratio of helper to suppressor T cells, absolute numbers of helper T cells, and T cell function in vitro. Seven of 18 patients who were seronegative in 1983 had seroconverted by 1984. The relative risk of seroconversion for patients using any concentrate since 1981 compared with those using cryoprecipitate only was 3.9 (P = .04). Nevertheless, the rate of conversion in the latter group was 18% per year.     

Impaired immune function in hemophilia patients treated exclusively with cryoprecipitate: relation to duration of treatment

Recently, abnormalities of cell-mediated immunity were found in hemophiliac patients receiving factor VIII concentrate therapy. Contradictory results were reported concerning cellular immune functions in hemophiliacs treated only with cryoprecipitate or fresh frozen plasma. Therefore, we evaluated the immunological status of 15 Israeli patients with severe classic hemophilia-A who were treated only with cryoprecipitate and never exposed to factor VIII concentrate whether of commercial source or blood bank prepared. As a group, only mildly depressed cellular immune functions and slight reduction in the helper to suppressor cell ratio were found. However, when patients treated more than 15 years were analyzed separately, a significant reduction in proportion of T cells, T-helper cells, helper to suppressor ratio, and proliferative response to phytohemaglutinin and pokeweed mitogen were observed compared to patients treated for less than 15 years and normal controls. Proportion of T-suppressor cells, Con A-activated suppressor activity, and IgG and IgA levels were significantly elevated in patients treated for more than 15 years. These results may support the view that derangement of immune function in hemophiliacs results from infusion of foreign proteins or an ubiquitous virus rather than contracting AIDS infectious agent.     

冷沉淀在门奇静脉断流术治疗门静脉高压患者中的应用

目的探讨使用冷沉淀对降低门奇静脉断流术围手术期大出血等风险的作用,及其对术后并发症的影响。方法68例门脉高压患者实施脾切除、门奇静脉断流术。患者随机分为两组,34例为冷沉淀使用组,于术中输注冷沉淀10单位;34例为对照组,术中不使用冷沉淀。比较两组患者术后创面出血情况、凝血酶原时间、术后恢复情况及消化道再出血、门静脉系统血栓等并发症的发生率等。结果与对照组比较,输注冷沉淀的门奇静脉断流患者,术后创面失血明显减少,腹腔内及消化道大出血的发生率降低。患者恢复较快,术后平均住院日低于对照组。门静脉系统血栓等并发症不高于对照组。结论门奇静脉断流术中输注冷沉淀可改善凝血机能,有效预防围手术期大出血的发生,有助于患者术后恢复。其使用未增加门静脉系统血栓等并发症的发生,安全有效。     

Immunologic studies of rheumatoid arthritis patients treated with methotrexate

Immunologic functions of peripheral blood mononuclear cells were studied in rheumatoid arthritis (RA) patients treated with methotrexate (MTX). Spontaneous IgM rheumatoid factor (IgM-RF) synthesis by unstimulated cultured blood mononuclear cells was seen in only 3 of 18 MTX-treated patients, compared with 31 of 54 RA patients who were not receiving long-acting drugs. Total IgM production by unstimulated cultured mononuclear cells, pokeweed mitogen-induced antibody synthesis, and plasma levels of IgM-RF were also lower in MTX-treated patients than in other RA patients. The numbers of circulating B cells, T4 and T8 cells, the T4:T8 cell ratio, and mitogen-induced proliferation indices were similar in MTX-treated and non-MTX-treated patients. Eleven additional patients were studied prospectively after initiation of MTX therapy. All showed significant decreases in spontaneous IgM-RF synthesis, with declining IgM-RF:IgM ratios, including all of the 9 who were studied during the first 24 hours of treatment. The results indicate that MTX has rapid effects on IgM-RF synthesis, and this action might be associated with its therapeutic efficacy in RA.     

Immunologic aberrations, HIV seropositivity and seroconversion rates in patients with hemophilia B

Because there have been reports that factor IX concentrate is less immunosuppressive and therefore factor IX users have less immunologic aberrations, we have studied a group of 22 patients with hemophilia B and six patients with factor VIII deficiency and high titer inhibitors with respect to lymphocyte numbers and function, human immunodeficiency virus (HIV) serology, and factor usage. This group was compared to 111 patients with hemophilia A and a group of 28 healthy male volunteer controls. When the study began in 1983, the majority of patients with hemophilia B and with higher titer factor VIII inhibitors were seronegative, 77% and 83% respectively, as compared to only 30% of patients with hemophilia A. At that time the factor IX users also had milder immune aberrations than the hemophilia A group. However, with time and increasing clotting factor concentrate usage, seroconversion and more striking abnormalities in immune function have occurred in the hemophilia B group. In a subgroup of 16 patients with hemophilia B studied twice, the incidence of seropositivity increased from 31% in 1983 to 69% in 1985. We thus conclude that factor IX concentrate in itself is not less immunosuppressive than factor VIII concentrate. Seroconversion in factor IX concentrate users appears to be lagging behind seroconversion in factor VIII concentrate users, perhaps secondary to the lower cumulative dosage of concentrate that patients with hemophilia B utilize.     

HIV infection in Norwegian haemophiliacs: the prevalence of antibodies against HIV in haemophiliacs treated with lyophilized cryoprecipitate from volunteer donors

334 of 389 (86%) registered Norwegians with coagulation factor defects were screened for antibodies to the human immunodeficiency virus (HIV) in 1985/1986. 21 persons were confirmed anti-HIV positive. They were all persons with clinically severe haemophilia A and represent 18.4% of 114 tested persons with severe haemophilia A. 3 patients have developed AIDS, 3 have persistent generalized lymphadenopathy. At least 8 of the 21 seropositive persons (38%) have been infected through lyophilized cryoprecipitates prepared from volunteer plasma donated in national blood banks. None of 10 heterosexual partners have antibodies to HIV. We conclude that the policy of using small-pooled lyophilized cryoprecipitates instead of commercial concentrates has reduced HIV-infection among Norwegian haemophiliacs. Today, the prevalence of HIV antibodies in the haemophilia population in Norway is among the lowest in Western Europe.     

Immunologic status of patients with pulmonary tuberculosis and pneumonia]

A combined immunologic examination included 67 patients with concurrent lung pathology (tuberculosis with pneumonia), 64 with tuberculosis and 71 with pneumonia. The relation of the immune status to the pattern of the process was demonstrated proceeding from the findings. Pneumonia in the abatement phase had no influence on the immunologic parameters of a tuberculosis patient. Acute pneumonia combined with tuberculosis was marked by suppressed T-lymphocyte functional and specific activity, increased counts of T-suppressors and the presence of antituberculous antibodies. It was found that the newly developed diagnostic tables can be used effectively for differentiating the combined pathology from the uncomplicated tuberculosis and pneumonia.     

Immune tolerance in a haemophilia A patient with high inhibitor using locally prepared lyophilized cryoprecipitate

The immune tolerance in a 12-year-old haemophilia A patient was carried out at the Faculty of Medicine, Ramathibodi Hospital, Bangkok in 1998. His inhibitor titres ranged from 10 to 3450 Bethesda units (BU). He suffered from serious bleeding episodes requiring prolonged hospitalization and the disarticulation of the left knee joint. After obtaining informed consent, locally prepared lyophilized cryoprecipitate (LC), heat treated at 60 degrees C for 25 h, was given in a dose of 13 units kg-1 body weight of factor VIII three times per week. His inhibitor was increased from 15 to 580 BU within the first 4 weeks of immune tolerance. Finally, it was decreased to 40 BU in the 36th week. The only adverse effect was seroconversion of anti-hepatitis C virus after receiving 108 bottles of LC for 36 weeks. In conclusion, the locally prepared LC was able to control the bleeding episodes in a haemophilia A patient with high inhibitor. To our knowledge, this is the first reported case in Thailand.     

经不同血管径路行冠状动脉介入治疗对患者心理状况的影响

目的经股动脉行冠状动脉介入治疗后,应用中国版90项症状清单(Symptom Checklist 90,SCL-90)评价发现患者的躯体化因子评分高于常模。本研究的目的是了解经不同血管径路行冠状动脉介入手术是否会影响患者的心理状况。方法本研究为非随机同期对照研究。198例因疑诊冠心病首次行冠状动脉造影或介入治疗的患者,其中经股动脉径路者105例,经桡动脉径路者93例。所有患者均于术前24 h内及术后24～48 h行中国版90项症状清单评价。根据数据的分布特点、基线指标分别采用x2检验或t检验进行两组间比较;采用双因素方差分析检验经不同血管径路及冠状动脉介入手术本身对患者SCL-90评分的影响。结果两组之间年龄、性别、体重、烟酒嗜好、职业、文化程度、婚姻状况、家庭关系、心脑血管病家族史、本人及家庭年收入以及医疗费用的支付方式(即是否有医疗保险)等方面差异均无统计学意义;两组间合并高血压和糖尿病的人数也无差别;确诊冠心病以及行冠状动脉介入治疗的患者数亦相似。与术前相比,冠状动脉介入手术后躯体化、强迫症状、人际关系敏感、抑郁、焦虑、敌对、总均分和阳性项目数等项目评分均有明显下降(分别为1.50±0.51比1.64±0.53;1.50±0.48比1.67±0.55;1.28±0.41比1.38±0.49;1.42±0.43比1.55±0.53;1.38±0.41比1.58±0.54;1.32±0.35比1.44±0.41;1.38±0.34比1.49±0.42;和23.08±17.30比27.72±18.79,P均<0.05)。与经股动脉径路相比,经桡动脉行冠状动脉介入手术显著减少躯体化、抑郁和阳性症状均分等项目评分(分别为1.52±0.51比1.62±0.53;1.43±0.54比1.54±0.43;2.36±0.66比2.50±0.43,P均<0.05)。结论经桡动脉行冠状动脉介入手术可减轻患者的躯体化及抑郁症状;冠状动脉介入手术后患者的心理症状明显减轻。     

Immunologic effects in patients with psoriatic arthritis treated with cyclosporine A.

Twelve patients with psoriatic arthritis (PsA) and very active articular disease resistant to conventional second line therapy entered into a 6-month open study of cyclosporine A (CsA) at a starting dosage of 3 mg/kg/day. Comparisons of phenotypic characteristics of lymphocytes and response to mitogens of peripheral blood mononuclear cells (PBMC) were made between these patients with PsA before CsA therapy, 7 patients without prior 2nd line therapy, 14 untreated patients with psoriasis alone, and 61 healthy controls. We confirmed a significant reduction of the basal percentage of CD8+ cells and an increase in the CD4/CD8 ratio in patients with PsA before CsA therapy compared to controls. These abnormalities were not present in patients with PsA without prior 2nd line therapy and in patients with psoriasis alone. Peripheral blood activated T cells (CD3+, HLA-DR+), natural killer (NK) (CD3-, CD16+ and/or CD56+), total B and CD5+ B cells were decreased only in patients with PsA before CsA therapy. The reduction of non-MHC restricted cytotoxicity T (CD3+, CD16+ and/or CD56+) was observed in all the 3 groups of patients compared to controls. After the 6 months of CsA therapy we observed a significant increase of CD3+, HLA-DR+, CD3+, CD16+ and/or CD56+, total B, and CD20+, CD5+ cells in the 11 patients with PsA compared to pretreatment values. Contrary to azathioprine, CsA does not impair the NK cell population which has a protective role against cancer and viral infections.     

Immunologic parameters of response in patients with rheumatoid arthritis treated with cyclosporin A

Thirty-one patients with seropositive rheumatoid arthritis treated with cyclosporin A (CsA) were evaluated for immune function prior to, during, and after 1 year of therapy. Patients whose pretreatment peripheral blood mononuclear cells were hypoproliferative in vitro to soluble recall antigens responded better clinically to CsA treatment than did the other patients. During therapy, proliferative responses became normal and remained so until 1-2 months after CsA was discontinued. At that time, the lymphocyte proliferation defect reappeared. In addition, patients who responded clinically to CsA had a higher percentage of Leu-7+ natural killer cells in their peripheral blood prior to therapy. All patients exhibited greater frequencies of cells that expressed interleukin-2 receptors, which decreased with CsA treatment. The clinical response to CsA appears to be associated with distinct immunologic parameters in rheumatoid arthritis.     

Studies of factor IX concentrate therapy in hemophilia

The effects of factor IX concentrate therapy on hemostasis in hemophilia patients were studied by means of the radiometric factor IXa assay, the coupled amidolytic assay for factor VIIa, and coagulant assays for factors II, IX, and X, and antithrombin III. Both activated and unactivated concentrates contained factors VIIa and IXa, with the highest levels in the activated concentrates. Factors VIIa and IXa were detected in patient plasma after infusion of unactivated concentrates. Increases of 3-5--fold in factors II and X were also found. Major decreases in antithrombin III activity, but not antigen, were found after unactivated concentrate therapy. This functional decrease may be due to the presence of inactive antithrombin III complexes, since a decreased mobility of antithrombin III antigen by crossed immunoelectrophoresis was found. These studies support the possible importance of factors IXa and VIIa as therapeutic agents and suggest that a transient functional deficiency in antithrombin III may be involved in the thrombotic potential of the concentrates.     

Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding

This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000–4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47–759) and 159 ng/ml (45–255). Median International Normalised Ratio pre- and post-PCC in patients on warfarin were 3·4 (1·9–15·4) and 1·2 (1·0–1·9). Blood products use was the same between groups. Thirty-day mortality and re-bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post-PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30-day mortality, re-bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.     

Long-term follow up of patients treated with intermediate FVIII concentrate BPL 8Y

Long-term surveillance studies of clotting factor concentrates are important to detect infrequent or delayed complications and to provide data against which newer products can be compared. We have assessed the long-term use of BPL 8Y factor VIII (FVIII) concentrate (Bio Products Limited, Elstree, UK) in a cohort of 33 patients. These patients have been treated for a median of 96 months. They have received between one batch (in total) and 10 batches per year and between 1020 units (in total) and 116 700 units per year of BPL 8Y concentrate. No patient has developed a clinically significant FVIII inhibitor. There has been no evidence of transmission of hepatitis C, hepatitis B or HIV 1 or 2. Parvovirus B19 IgG antibody was present in 100% of the patients screened. Analysis of CD4 and CD8 lymphocyte subsets, using age-related normal ranges, showed persistently depressed values in five patients, one of whom had a consistently low CD4/CD8 ratio.     

Antioxidant status of hypercholesterolemic patients treated with LDL apheresis

Summary Oxidation of low density lipoprotein is involved in the pathogenesis of atherosclerosis. Epidemiological studies suggest a negative correlation between the occurrence of cardiovascular diseases and blood concentrations of lipophilic antioxidants such as vitamins A and E and -carotene. Trace elements, such as selenium, zinc, and copper, are involved in the activity of the antioxidant enzymes glutathione peroxidase and superoxide dismutase. The aim of this study was to determine the antioxidant and trace element status of patients with severe hypercholesterolemia who had been treated with dextran-sulphate low-density lipoprotein apheresis in comparison with two control populations, normocholesterolemic subjects and untreated hypercholesterolemic patients. Our results showed that, patients treated with LDL apheresis, compared with normocholesteromic subjects, were not deficient in vitamin E, -carotene, and copper, but had low plasma levels of selenium, zinc, and vitamin A. The low selenium and vitamin A levels were due to the LDL-apheresis treatment, and the hypercholesterolemia might have provoked the low plasma levels of zinc. This study pointed out the potential benefits of supplemental selenium, zinc, and vitamin A in patients being treated with LDL apheresis.