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H H Brackmann

Publications and source records attributed to H H Brackmann.

At least 55 records · Page 3Linked to original sources
PubMed1999

Induction of immune tolerance in haemophilia A inhibitor patients by the 'Bonn Protocol': predictive parameter for therapy duration and outcome.

The treatment of inhibitors is one of the most challenging fields in haemophilia care. The present study reports the results of 60 haemophilia A inhibitor patients treated according to the 'Bonn Protocol' and evaluates predictors for the duration and outcome of therapy. Successful immune tolerance could be achieved in 52 patients (86.7%) while the therapy failed in eight patients (13.3%). The immune tolerance achieved was longlasting in all 52 patients, with no inhibitor relapse in up to 20-years follow-up. The course of ITT was influenced by several factors. Interruptions of treatment during the ITT course led to a substantial prolongation of ITT duration (median 39.9 months vs 14.1 months in continuously treated patients). Infections of intravenous central lines appeared to be frequently coincided with ITT prolongation and sometimes even ITT failure. Further negative predictors towards the ITT duration were high inhibitor titres at enrollment or during ITT. There was also a tendency towards longer ITT duration in patients exhibiting the prevalent intron 22 inversion. As a consequence of our data treatment interruptions and infections of intravenous central lines should be avoided during the course of ITT. Furthermore our data suggest, that ITT should be started at low inhibitor titres preferably with a high factor VIII dosage protocol.

Blood Coagulation Factors↗
PubMed1999

Inhibitors in German hemophilia A patients treated with a double virus inactivated factor VIII concentrate bind to the C2 domain of FVIII light chain.

To reduce the risk of transmission of hepatitis A virus, an Octapharma produced factor VIII (fVIII) concentrate treated with solvent detergent (FVIII-SD) was further pasteurized after purification. This product, Octavi SDPlus (FVIII-SDP), was marketed in Europe in 1993 to 1995. Inhibitors appeared from September to October, 1995, in 12 of 109 previously treated German hemophilia A patients. A study of similarly treated Belgian patients, who also developed inhibitors, had shown antibodies to the fVIII light chain (domains A3-C1-C2) only. In the present study, the epitope specificity of 8 German inhibitor plasmas was also found to be restricted to the light chain. In radioimmunoprecipitation assays to localize the light chain epitope(s), antibody binding to heavy chain (domains A1-A2-B) was 11-148 fold lower than to the C2 domain, and binding to recombinant A3-C1 was barely detectable. These results were supported by >95% neutralization of a high responder inhibitor titer by the C2 domain.

Adolescent↗
PubMed1998

[Acute posterior wall infarct after factor VIII concentrate administration to a patient with severe hemophilia A].

HISTORY AND CLINICAL FINDING: A 69-year-old man with severe haemophilia A sustained an acute myocardial infarction (MI) after self-administration of 3000 units factor VIII over 10 min. On admission he had no signs of heart failure. INVESTIGATIONS: The ECG showed an acute posterior wall MI. Creatinekinase rose to a maximum of 321 U/l with a significant MB proportion. The echocardiogram demonstrated hypokinesia of the posterior wall. TREATMENT AND COURSE: After initial thrombolysis treatment with a total of 100 mg rtPA according to an accelerated scheme coronary angiography, performed because the symptoms persisted, revealed two-vessel disease. A subtotal stenosis of the right coronary artery was balloon-dilated with good primary results. Regular factor VIII substitution was temporarily administered with the aim of initially achieving high normal levels of factor VIII activity. CONCLUSION: Factor VIII substitution in haemophilia A may promote thrombotic complications. Thrombolytic treatment and balloon angioplasty of acute MI can be successfully performed even in patients with severe haemophilia A.

Aged↗
PubMed1998

In vitro cytopathogenicity of the human immunodeficiency virus (HIV)-1 predicts survival in HIV-infected hemophiliacs independent from CD4 cell count.

In addition to quantification of viral load the graded cytopathogenicity of the human immunodeficiency virus may provide prognostic information for the course of HIV infection. However, the prognostic value of graded cytopathogenicity in addition to the CD4 count has not been evaluated in a large longitudinal study. Therefore a total of 216 HIV-seropositive hemophiliacs have been followed up from 1985 to 1998 (mean follow-up 70.4 +/- SD 26 months, median 72, range: 12 to 120 months). In vitro virulence was determined according to cytopathic effects on freshly isolated PBMC of healthy donors and graded from A (strongest cytopathogenic effect) to D (no cytopathic isolate effect). Survival was analyzed among patients with different virus isolates by Kaplan-Meier statistics (log rank) and factors independently associated with decreased survival were analyzed by Cox hazard regression analysis. - A virus isolate A was found in 22 (10.2%) patients, a virus isolate B was found in 21 (9.3%) patients, a virus isolate C was found in 9 (4.2%) and a virus isolate D was found in 10 (4.2%) patients. Mean survival times were 48 months (95% Confidence Interval (CI) = 36 - 60) in patients with isolate A, 72 months (CI = 36 - 108) with isolate B, 84 months (CI = 48-120) with isolate C, 72 months (60 - 96) with isolate D and 96 months (CI = 96 - 108) in patients with a negative virus culture (p < 0.001). Cox regression analysis indicated significant associations with outcome for young age (p <0.001), positive virus culture (p < 0.0001) and CD4 count (p < 0.0001) as independent predictors of survival. The presence of an isolate A revealed the strongest odds ratio (6.3, 95% CI 2.9-13.2). Our data indicate that the presence of a virus isolate A represents a strong risk factor for mortality in the course of HIV infection. Besides quantification of viral load and CD4 count, the graded cytopathogenicity may provide additional information for early and aggressive antiretroviral treatment, since the mean survival in patients with cytopathogenic virus isolates is reduced significantly.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Control of the synovium in haemophilia.

Adequate factor substitution is a prerequisite for successful conservative or operative treatment of haemophilic synovitis. Subsequent prophylactic factor substitution can prevent further joint problems in the future. Orthopaedic treatment regimes are dependent on the classification of the synovitis and the stage of the arthropathy. Synovitis can be classified into acute and chronic forms. The arthropathy is classified according to Arnold and Hilgartner. When the synovitis has already become chronic, early arthroscopic synovectomy is recommended in order to prevent the otherwise inexorable progress of the arthropathy. Failure to treat in the early phase of the pathology causes problems in the correction of further stages. The progression of the joint disease can be shown both clinically and radiologically as the arthropathy develops, and influences the treatment.

Hemophilia A↗
PubMed1998

Pharmacokinetics of azidothymidine and its major metabolite glucuronylazidothymidine in hemophiliacs coinfected with human immunodeficiency virus and chronic hepatitis C.

The increasingly reported cholestatic course of liver disease in hemophiliacs coinfected with human immunodeficiency virus (HIV) and hepatitis C (HCV) has been linked with impaired azidothymidine (AZT) metabolism in this patient group. Therefore, we compared the pharmacokinetics of AZT and its glucuronidated metabolite (glucuronylazidothymidine [GAZT]) in HIV/HCV-coinfected hemophiliacs without cirrhosis to HIV-infected patients without chronic hepatitis. Sixteen HIV/HCV-coinfected hemophiliacs without cirrhosis and six HIV-infected patients with negative hepatitis serology and normal liver transaminases received a single 100-mg oral dose of AZT. Subsequently, plasma concentrations of AZT and GAZT were measured during a 6-hour period by high-pressure liquid chromatography (HPLC). Blood samples were taken before and 30, 60, and 90 minutes and 2, 3, 6, and 8 hours after the intake of AZT. Pharmacokinetic parameters of AZT in HIV-infected patients with concomitant chronic hepatitis did not differ significantly as compared to patients without concomitant liver disease. GAZT half-life and mean residence time of GAZT, however, were significantly longer in HIV/HCV-coinfected hemophiliacs as compared to HIV-positive controls without hepatitis. In HIV-infected patients, underlying chronic hepatitis C does not require AZT dose adaptation. Yet despite normal oral clearance of AZT and GAZT, the increase of half-life and mean residence time of GAZT indicates a prolonged hepatic release of GAZT into the circulation of HIV-infected hemophiliacs with noncirrhotic hepatitis C.

Adult↗
PubMed1998

Immune tolerance induction: a role for recombinant activated factor VII (rFVIIa)?

The development of factor VIII (FVIII) and FIX inhibitors is one of the most serious complications of repeated transfusions in patients with haemophilia. Management of patients with haemophilia with inhibitors must be separated into 2 concepts: the control of acute bleeding episodes and, in the long term, the treatment of the inhibitor itself. This paper will discuss both aspects of the management of these patients, focusing in particular on the therapeutic options available for the treatment of bleeding episodes during immune tolerance induction (ITI) therapy. The second part of the paper will review the management and outcomes of 10 patients with severe haemophilia in whom recombinant activated FVII (rFVIIa: NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used to treat bleeding episodes in the Haemophilia Centre at Bonn University; 6 patients were treated with rFVIIa for bleeding episodes while undergoing ITI. The results obtained demonstrate that rFVIIa is a safe and effective treatment for bleeding episodes and haemostatic cover for surgical procedures in patients with inhibitors. Inhibitor titres were not boosted in patients with haemophilia and inhibitors on treatment with rFVIIa. Therefore, rFVIIa is also a suitable treatment for bleeding episodes or control of haemostasis during surgery in patients prior to initiation of ITI therapy.

Antibodies↗
PubMed1997

Systemic delivery of human growth hormone or human factor IX in dogs by reintroduced genetically modified autologous bone marrow stromal cells.

Canine bone marrow stromal cells were expanded to numbers in excess of 10(9) cells from the initial 10-20 ml of marrow aspirates and transfected to express high levels of human growth hormone (hGH) in vitro. Ex vivo-modified marrow stromal cells were used in a gene therapy model system for the systemic delivery of transgene products in dogs. Adherent bone marrow stromal cell cultures, established and expanded from iliac crest marrow aspirates from each of 8 dogs, were transfected with a hGH gene plasmid expression vector and shown to express from 0.54-3.84 micrograms/10(6) cells per 24 hr hGH in vitro. The transfected plasmid vector does not possess a eukaryotic origin of replication nor does it possess sequences required for efficient integration into the host cell genome. As such, expression was expected to be transient. Transfected cells were autologously reintroduced into each dog by either infusion into a foreleg vein or directly into iliac crest marrow. In two cases, the stromal cells were cryopreserved following transfection, and subsequently thawed and infused. In one case, the expanded stromal cells were first cryopreserved, and then thawed, recultured, transfected, and infused. Reintroduced cell numbers ranged from 2.2 x 10(7) to 2.6 x 10(9), with total hGH expression capacities ranging from 62 to 1,400 micrograms/24 hr. Plasma of each of the dogs contained detectable hGH for a mean of 3.1 days (SD +/- 0.8 day) ranging from 2 to 5 days following reinfusion of cells. Peak plasma levels ranged from 0.10 to 1.76 ng/ml. Similar hGH expression values, based upon total expression capacity of the cells infused and dog body weight, were obtained for all dogs. Vector-modified stromal cells were detectable, by polymerase chain reaction (PCR) analysis, in the peripheral circulation following reinfusion in all 4 dogs analyzed. In 3 of the dogs, modified stromal cells were detected for 8.5-15 weeks. In addition, modified stromal cells were detected in iliac crest marrow of 2 dogs for 9 and 13 weeks, respectively, following reinfusion. In another experiment, cultured bone marrow stromal cells were transfected with a human factor IX (hFIX) plasmid vector. Modified cells (5.57 x 10(8)), with a total hFIX expression capacity of 281 micrograms/24 hr, were reinfused, resulting in detectable hFIX in plasma continuously for 9 days with a peak level of 8 ng/ml on day 1. These results demonstrate that the ex vivo bone marrow stromal cell system is a potentially powerful method by which to deliver secreted transgene product to the systemic circulation of large animals.

Animals↗
PubMed1997

Liver histopathology in patients with concurrent chronic hepatitis C and HIV infection.

To investigate the influence of human immunodeficiency virus (HIV) coinfection on preexisting long-term chronic C hepatitis (HCV) 68 liver biopsies from 22 HIV/HCV-coinfected, 13 HIV- and 33 HCV-monoinfected patients and 71 livers obtained at autopsy from 26 HIV/HCV-coinfected and 45 HIV-monoinfected patients were studied by histo- and immunohistochemistry. All HIV patients had reached the advanced stage of immunodeficiency (stage III CDC), except for 3 haemophilias (stage II CDC). HCV infection was associated with a higher degree of portal, periportal and lobular inflammation-regardless of whether there was concurrent HIV infection. HIV/HCV coinfection was associated with a significantly higher rate of granulocytic cholangiolitis than HCV and HIV monoinfection (P < 0.05), a histological feature uncommon in C hepatitis. In HIV/HCV coinfection cholestasis was a predominant histological feature. HCV monoinfection and HCV/HIV coinfection were associated with the highest fibrosis index. In HIV/HCV coinfection centrilobular fibrosis was significantly more marked than in HCV monoinfection (P < 0.05), suggesting an HIV-associated fibrogenic effect. Patients with chronic C hepatitis showed a significantly increased rate of posthepatitic cirrhosis compared with the patients without HCV infection (P < 0.05). At autopsy, 10 of the 20 HIV/HCV-coinfected haemophiliacs had developed cirrhosis because of chronic C hepatitis, whereas cirrhosis was found in only 2 of 6 HIV/HCV-coinfected non-haemophiliacs (1 case of chronic B and C hepatitis, and 1 case of chronic alcohol abuse). No cirrhosis was observed in the 45 autopsy patients with HIV monoinfection. The findings suggest that HIV coinfection aggravates the course of preceding long-term chronic C hepatitis by a more marked (centrilobular) fibrosis. HIV/HCV-coinfected patients are threatened by a higher rate of posthepatitic cirrhosis-particularly in multitransfused haemophiliacs-and cholestatic hepatopathy.

Adolescent↗
PubMed1997

Factor VIII gene mutations found by a comparative study of SSCP, DGGE and CMC and their analysis on a molecular model of factor VIII protein.

Screening of the factor VIII (FVIII) gene which spans 186 kb and codes for 26 exons, was originally hampered by its size but is now feasible because rapid DNA scanning methodologies have been developed. The present study for the first time directly compares the three most widely applied screening methods, denaturing gradient gel electrophoresis (DGGE), single-stranded conformational polymorphism (SSCP) and chemical mismatch cleavage (CMC) for their sensitivity of mutation detection in a selected group of ten haemophilia A patients. Nine of these patients are known to be cross-reacting material positive and eight exhibited a mild to moderate phenotype. Of the ten patients screened, we identified mutations in nine by all three screening methods. Of the mutations characterised, two are previously unpublished. T to C (S373P) and G to A (D525N). In one mildly affected haemophiliac, we identified a second T to C sequence change in the 5' untranslated region at -601 bp, probably having no effect on FVIII gene expression. Modelling studies were performed on those mutations lying within the A domains of FVIII (D525N, R527W, I566T) to study the possible effect of these mutations on structure and/or function. When the three methods are performing optimally and have been standardised, our experience is that CMC and DGGE are equally efficient at sequence variation detection while SSCP is slightly less sensitive.

Computer Simulation↗
PubMed1997

Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy.

Bleeding complications are the most common and unwanted side-effect of oral anticoagulant therapy. We report three patients in whom mutations in the factor IX (FIX) propeptide were found to cause severe bleeding during coumarin therapy. Strikingly, the bleeding occurred within the therapeutic ranges of the prothrombin time (PT) and international normalized ratio (INR). In all three patients coumarin therapy caused an unusually selective decrease of FIX activity (FIX:C) to levels below 1-3%. Upon withdrawal of coumarin, FIX:C increased to subnormal or normal values of 55%, 85% and 125%, respectively. Analysis of the FIX gene revealed two different missense mutations affecting the Ala-10 residue in the propeptide coding region: Ala[GCC] to Val[GTC] in two patients and Ala[GCC] to Thr[ACC] in one patient. No further mutation was detected by screening 195 random blood donors for mutations at Ala-10, thus excluding a frequent polymorphism at this position. The mutation in the FIX propeptide at a position which is essential for the carboxylase recognition site causes a reduced affinity of the carboxylase enzyme to the propeptide. This effect leads to an impaired carboxylase epoxidase reaction which is decisively triggered by the vitamin K concentration. Determination of FIX and APTT in addition to PT and INR is therefore recommended in coumarin-treated patients with an uncommon bleeding pattern.

Administration, Oral↗
PubMed1997

HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII.

Molecular genetic studies have shown that development of antibodies to factor VIII (inhibitors) occurs most frequently in patients with severe haemophilia due to major gene lesions including inversions, stop codons and large deletions. Previous studies of HLA type were performed on inhibitor and non-inhibitor patients with diverse uncharacterized mutations which may have confounded detection of significant associations. We therefore selected a group of patients with a single mutation type, the prevalent intron 22 inversion, with or without inhibitors, to determine HLA genotype. Seventy-one such patients, 42 without and 29 with inhibitors (13 high, 9 low and 7 transient responders) were genotyped for MHC Class I HLA-A, -B, -C and Class II HLA-DQA, -DQB and -DRB loci. No strong correlation of any HLA-allele to inhibitor or non-inhibitor status was found. However, alleles of the haplotype HLA-A3, HLA-B7, HLA-C7, HLA-DQA0102, HLA-DQB0602, HLA-DR15 occurred more often in inhibitor patients. Since the alleles of this extended haplotype are common in the North European population only a very strong association would achieve statistical significance. Further studies of groups of patients similar to those studied here will be needed to confirm or exclude this association.

Alleles↗
PubMed1997

Arthroscopy for chronic hemophilic synovitis of the knee.

Between 1988 and 1995, 32 knee joints (29 patients) with hemophilic arthropathy underwent arthroscopy. The spectrum of procedures ranged from resection of fibrous plicae to synovectomy. Technical difficulties appeared in cases of scarred fixed patella, pronounced posterior tibia subluxation, and severe fibrous ankylosis. All operations done between 1988 and 1991 (23 operations; 21 patients) were reviewed retrospectively. The mean age of the patients in this series was 30 years and the mean followup was 5 years. On subjective evaluation, 13 operations achieved a definite improvement, five showed slight improvement, and two had no improvement (three operations were excluded). Arthroscopic surgery, as a relatively low risk technique, combined with early functional rehabilitation, can be used to achieve satisfactory results in patients with hemophilic arthropathy.

Adolescent↗
PubMed1997

Gait analysis of the hemophilic ankle with silicone heel cushion.

Shock absorption becomes very important in damaged joints with destroyed cartilage and progressive muscular imbalance as occurs in hemarthropathy. The effects of silicone heel cushioning on the ankle motion of hemophilic patients in different stages of hemarthropathy of the ankle joints was measured using an ultrasound motion analysis system. It is concluded that silicone heel cushioning has no influence on ankles in the late stage of hemarthropathy. Silicone heel cushioning will lead to uncontrolled changes of the ankle joint in the early hemarthropathic ankle, involving the tibiotalar and the subtalar joints. The angular velocity of the ankle is increased producing higher acceleration at the ankle joint. The higher angle acceleration is related to higher joint loading uncontrolled by the muscles. The resulting uncoordinated motion can cause ligamentous overloading, strains, and a higher probability of joint bleeding. Therefore, silicone heel cushioning or other shock absorbing devices that return the energy immediately to the foot are not useful for prevention and treatment of chronic hemophilic synovitis and may cause additional deterioration of the joint.

Acceleration↗
PubMed1996

The prevalence of antibody to parvovirus B19 in hemophiliacs and in the general population.

The prevalence of antibodies to parvovirus B19 (B19) was measured in the sera of 566 hemophiliacs and 524 individuals of the general population by immunofluorescence assays, using antigen expressed by the baculovirus system. In the general population, anti-B19 IgG seroprevalence was found to continuously decline from 64 percent at birth to 0 percent in the age of 9-11 months and thereupon to increase to 61 percent in the age of 12 years. In younger adults and older people, IgG seroprevalence only slowly increased with age, reaching 77 percent in people aged 60 and above. In contrast, in hemophilic children treated exclusively with virally inactivated clotting factor concentrates, neither decrease nor increase of B19 IgG antibody was detectable and the overall seroprevalence was 92 percent. In the group of hemophiliacs older than 12 years and treated before 1984 with non-inactivated clotting factor concentrates, 98 percent showed antibody to B19. Anti-B19 IgM seroprevalence was significantly higher in hemophilic than in non-hemophilic individuals older than 12 years. Since it seems to be unlikely that the high seroprevalence in hemophiliacs is acquired by immunization with inactivated viral antigen, the results suggest that infection with B19 is transmitted by clotting factor concentrates, even if subjected to virucidal methods.

Adolescent↗