To learn more about prioritisation in the health care system, we performed an exploratory qualitative study on haemophilia A. The aim was to generate haemophilia disease-specific criteria and to learn more about reasoning in the decision-making process. The 40 participants (patients, relatives, physicians, nurses) were asked in semi-structured interviews about their experiences regarding the German health care system in general and the management of haemophilia A. The 4 stakeholder groups agreed that treatment in haemophilia A was very good; there were complaints about increased bureaucracy. Arguments originated in personal past experiences (patients, relatives) and in the professional background (healthcare professionals). Decision-making criteria ranking high were the maintenance of mobility, social responsibility and the prospect of a long working life span. Criteria with lower ranking were a high social professional status and age. There was ambivalence as to whether savings in the healthcare system in general were necessary or inacceptable. Prophylactic factor administration was rejected when high-risk sports were practiced regularly. Decision-making among actual individuals was rejected as ‘immoral’. Patient representatives should be included in the political decision-making process. In conclusion, solidarity in the German health insurance is a highly esteemed principle, but was not well comprehended. The findings demonstrate the variety of individual attitudes with strong context affinity to the disease and the background of the stakeholder groups. The challenge will be to find ways of prioritising in an accountable and transparent way to maintain an excellent health care service for the individual haemophilia patient while also serving the public good.

Protein S (PS) is a vitamin K-dependent glycoprotein with a molecular mass of about 78 kDa. The human PS gene, PROS1, is located on chromosome 3q11.2, where it spans 80 kb of genomic DNA and contains 14 introns and 15 exons [ 1 Schmidel D.K. Tatro A.V. Phelps L.G. Tomczak J.A. Long G.L. Organization of the human protein S genes. Biochemistry. 1990; 29: 7845-7852 Crossref PubMed Scopus (128) Google Scholar , 2 Hartz PA. Personal Communication Baltimore, Md, 9/30/2008. Google Scholar ]. The protein functions as a cofactor for activated protein C (APC), an anticoagulant serine protease, which regulates blood coagulation by inactivating factors Va and VIIIa [ [3] Walker F.J. Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem. 1980; 255: 5521-5524 Abstract Full Text PDF PubMed Google Scholar ]. PS is found in plasma both in a free form (30%) and complexed with C4b-binding (C4BP) protein [ [4] Dahlback B. The tale of protein S and C4b-binding protein, a story of affection. Thromb Haemost. 2007; 98: 90-96 PubMed Google Scholar ]. Recently, it has been described that not only the free form but both forms work as cofactors for activated protein C [ [5] Maurissen L.F. Thomassen M.C. Nicolaes G.A. Dahlback B. Tans G. Rosing J. et al. Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation. Blood. 2008; 111: 3034-3041 Crossref PubMed Scopus (59) Google Scholar ]. Certain mutations in this gene result in autosomal dominant hereditary thrombophilia. PS deficiency affects up to 2% of families with congenital thrombophilia [ [6] Pabinger I. Brucker S. Kyrle P.A. Schneider B. Korninger H.C. Niessner H. et al. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinolysis. 1992; 3: 547-553 Crossref PubMed Scopus (150) Google Scholar ]. Erratum to "Clinical consequences of compound heterozygosity for protein S mutation Heerlen and p.Cys252Gly protein S mutation" [Thrombosis Research 128 (2011) 498–500]Thrombosis ResearchVol. 130Issue 1PreviewDue to an error in the publisher's style guide, the order of authors for the above Letter was incorrectly reproduced in the print version of the journal. The correct order is given above. Full-Text PDF

Die aktuelle Debatte um Rationierung oder Priorisierung medizinischer Leistungen berührt die Frage nach dem Solidarprinzip der GKV und dem Solidaritätsverständnis ihrer Versicherten. Der vorliegende Beitrag stellt Ergebnisse einer empirischen Untersuchung zum Solidaritätsverständnis von Stakeholdern der Hämophilie A vor. Für die Untersuchung wurden die in einer qualitativen Interviewstudie zur Priorisierung medizinischer Leistungen am Beispiel der Hämophilie A erhobenen Äußerungen gesondert auf das zugrundeliegende Verständnis von Solidarität untersucht. Die qualitative Inhaltsanalyse ergibt ein ambivalentes, zwischen den Ansprüchen des Einzelnen und der Gemeinschaft abwägendes Verständnis von Solidarität. Zum einen bewerten Interviewpartner eine vorrangige Behandlung von einzelnen Patienten als unsolidarisch denjenigen gegenüber, die nachrangig behandelt werden sollen. Zum anderen gilt eine übertriebene Inanspruchnahme GKV finanzierter Leistungen des Gesundheitssystems als unsolidarisch gegenüber der Solidargemeinschaft und wird abgelehnt. “Why should you pay for Insurance if you're not getting anything out of it” A Qualitative Study on the Attitude towards Solidarity in the Statutory Health Insurance in the Context of the Debate about Prioritisation This article presents the results of an empirical study of the views of haemophilia A stakeholders on solidarity. In our project, the comments given in a qualitative interview study on the prioritization of medical services in haemophilia A were examined with special emphasis on the basic understanding of solidarity. The qualitative content analysis reveals an ambivalent understanding of solidarity that differs between individual expectations and those of society as a whole. The interview partners tend to judge prioritization of individual patients as not being compatible with solidarity towards those ranking lower. But an unjustified use of resources provided and paid for by the health care system is also rejected.

The development of inhibitors in haemophilia B is one of the most important complications of replacement therapy, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors, and to date, only little is known about its underlying mechanisms. Here, we present first results of the haemophilia B group of our Inhibitor-Immunology study. Patients, methods: So far we have analysed 15 patients with haemophilia B. Four of them developed a high titre inhibitor; the remaining 11 had no inhibitor. We evaluated 9 SNPs in 8 genes (CD40, CTLA-4 , IL-1β, IL-10, TLR2 , TLR4, TLR9, TNF-α). We compared the distribution of these alleles between inhibitor and non-inhibitor haemophilia B patients and between haemophilia B patients and a normal male control population. HLA typing was performed in all patients. Results, discussion: There appears to be a trend towards a skewed distribution of TLR 9, IL-10 and CTLA4 alleles in haemophilia B patients. Due to the limited number these differences are, however, not statistically significant. The t-test of all patients with inhibitor versus without inhibitor was significant for HLA-A*03 and DPB1*0401 and borderline for DRB1*0201.

Im Zuge aktueller Reformen im Gesundheitswesen wurden Strukturen, Organisation und Leistungsspektrum der GKV neu gefasst. Die Änderungen werden von einer kontroversen gesundheitspolitischen und medizinethischen Debatte über Ursachen, Folgen und Konsequenzen, insbesondere in Form von Rationierung und Priorisierung medizinischer Leistungen, begleitet.

It is well known that the factor VIII activity (FVIII:C) is significantly reduced in about 20% of the female carriers of mutations in the F8 gene. Consequently these women are prone to bleeding after surgery or trauma and a factor VIII substitution could be indicated to avoid such complications. However, the question how many percent of women with reduced FVIII:C and negative family history for hemophilia A are carriers of a mutation in the F8 gene remains unresolved. In this report we face this important issue.

The congenital Factor VII deficiency (FVIID) is a rare hemorrhagic disorderwith an autosomal recessive pattern of inheritance and a prevalence of 1:500,000. In 1994 the International Greifswald Registry of congenital FVII deficiency was initiated [1]. We analyzed the phenotype and genotype of subjects,who presented with reduced FVII activities.

UNLABELLED:The development of inhibitors is one of the most important complications of replacement therapy in haemophilia, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors. Cytokines and their receptors, T-cell receptors, and the Major Histocompatibility Complex may play important roles in the development of inhibitors. Earlier studies showed non significant associations between HLA class and inhibitor development. Later studies found an increased risk of inhibitor development if there was a combination between certain factor VIII mutations and HLA antigens. We performed HLA typing in 50 patients with haemophilia A in an effort to find associations with inhibitor development.RESULTS:25 patients had developed an inhibitor (11 low titre, 14 high titre), and 25 never had. In logistic regression analysis, HLA-A 34, DRB1 0405, DRB1 1301 seemed to be involved in inhibitor development and HLA-A 30, B 13, B15, B 57, Cw 12, DQB1 0303, DPB1 0201 protection against inhibitor development. In our patients, the HLA-associations with inhibitor development were different from those in previous publications.

Successful home treatment in persons with hemophilia is not only depending on medical knowledge and technical skills, but also on the patients’ and parents’ willingness to share responsibility for treatment. The German Hemophilia Society (DHG) and the Hemophilia Care Center at Hanover Medical School are collaborating to enhance our patients’ capability and motivation for home treatment.

Background: Diagnosis of acquired von Willebrand syndrome (AVWS) remains challenging. Diagnostic algorithms suggest the use of factor VIII (FVIII:C), von Willebrand factor antigen (VWF:Ag), ristocetin cofactor (VWF:RCo), and collagen-binding capacity (VWF:CB), but the sensitivity of these and other laboratory tests for the diagnosis of AVWS is unknown. Objectives: To analyze the capacity of laboratory tests, including point-of-care testing (POCT), for the identification of patients with AVWS. Patients/methods: Thirty-five consecutive patients were enrolled with AVWS diagnosed because of a history of recent onset of bleeding, a negative family history of von Willebrand disease, and abnormal plasma VWF multimers. Results: According to our inclusion criteria, all patients had bleeding symptoms, and the VWF high molecular weight multimers were either decreased or absent. Regarding POCT, PFA-100 was inconclusive, due to anemia or thrombocytopenia, in 29%; the sensitivity was 80% in the remaining patients. The sensitivity of VWF:Ag (23%), VWF:RCo/Ag ratio < 0.7 (26%), VWF:CB/Ag ratio < 0.7 (46%), anti-VWF antibodies (15%) and VWF propeptide/Ag ratio (22%) was too low to rule out the disease. A combination of VWF:Ag < 50 IU dL(-1), VWF:RCo/Ag ratio < 0.7 and VWF:CB/Ag ratio < 0.8 yielded a sensitivity of 86%. Patients diagnosed only because of abnormal VWF multimers showed similar clinical characteristics as other patients. Conclusions: Early diagnosis of AVWS is difficult, due to lack of sensitivity of the tests used. A substantial number of patients present with normal or increased test results, emphasizing the importance of multimer analysis in all patients with suspected AVWS.

Acquired Glanzmann thrombasthenia is a rare bleeding disorder which is characterized by a blank bleeding history, rapid onset of bleeding tendency with a significantly prolonged bleeding time but normal platelet counts and normal expression of platelet membrane glycoproteins (GP). Etiologically, platelet antibodies bind on or close by the GP IIb and/or IIIa and inhibit binding of fibrinogen and von Willebrand factor (VWF) to platelets [1]. These antibodies mostly emerge in the scope of lymphoproliferative or autoimmune diseases. An association with a myelodysplastic syndrome (MDS) which we observed in our presented patient has not been described in the literature to our knowledge. This coincidence supports the thesis of loss of T cell regulation in MDS and establishes the basis for new immunosuppressive therapeutic approaches to acquired Glanzmann thrombasthenia.

The amount of residual F8 (FVIII:C) determines the clinical severity of hemophilia A. Recently, we showed that the mutation detection rate in severely affected male patients (FVIII:C<1% of normal) is virtually 100% when testing for the common intron 22-/intron 1- inversions and big deletions, followed by genomic sequencing of the F8 gene. Here we report on the spectrum of mutations and their distribution throughout the F8 gene sequence in 135 patients with moderate (n=23) or mild (n=112) hemophilia A. In contrast to the severe form of the disorder, analysis on the genomic level failed to detect the molecular defect in approximately 4% of the moderately and in approximately 12% of the mildly affected patients. A total of 36 of the mutations identified in this study are novel. The vast majority of the detected changes were missense. The newly detected amino acid substitutions were scored for potential distant or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling. Two molecular changes in the promoter region of the factor VIII gene (c.-112G>A and -219C>T), affecting the core segment (minimal promoter) were detected in two patients with mild hemophilia A. To our knowledge this is the first report on promoter mutations in the F8 gene.

Hemophilia A is the most frequently occurring X-linked bleeding disorder, affecting one to two out of 10,000 mates worldwide. Various types of mutations in the F8 gene are causative for this condition. It is well known that the most common mutation in severely affected patients is the intron 22 inversion, which accounts for about 45% of cases with F8 residual activity of less than 1%. Therefore, the aim of the present study was to determine the spectrum and distribution of mutations in the F8 gene in a large group of patients with severe hemophilia A who previously tested negative for the common intron 22 inversion. Here we report on a mutation analysis of 86 patients collected under the above-mentioned criterion. The pathogenic molecular defect was identified in all patients, and thus our detection rate was virtually 100%. Thirty-four of the identified mutations are described for the first time. The newly detected amino acid substitutions were scored for potential gross or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling.

ACE displays potent vasoconstrictive effects, attenuation of fibrinolysis, and platelet activation and aggregation, thus possibly promoting venous thromboembolism (VTE). The ACE gene contains an insertion (I) or deletion (D) polymorphism accounting for 50% of the variation in serum ACE concentration. To evaluate the role of the I/D polymorphism in VTE, its prevalence was determined in 931 patients with VTE and 432 blood donors. The prevalence of the DD genotype was 27.6% in patients and 21.3% in controls (OR 1.4; p < 0.02). In multivariate analysis there was a trend of the DD genotype to be an independent risk factor (OR 1.4; p = 0.08). No differences in DD genotype prevalence according to exogenous risk factors were found. Coinheritance of FV G1691A, PT G20210A mutation, and PS deficiency with the DD genotype increased the relative risk of VTE. Thus, the ACE DD genotype is a moderate risk factor of hereditary thrombophilia. Exogenous risk factors did not alter the manifestation of VTE among carriers of the DD genotype, whereas coinheritance of the DD genotype with the aforementioned defects increased the risk for VTE considerably.

SummaryFour new molecular abnormalities in the γ subdomain of the D domain elucidated in three unrelated thrombophilic patients and in one asymptomatic case of hypofibrinogenemia are reported: fibrinogen Suhl, γ 326,Cys →Tyr, fibrinogen Hannover VI, γ 336 Met →Ile, fibrinogen Stuttgart, γ 345, Asn→Asp and fibrinogen Homburg VII, γ354,Tyr→Cys. In all cases, fibrin polymerization in plasma is impaired. In the case of fibrinogen Suhl, there was a normalization of fibrin polymerization in plasma at higher Ca2+ concentration. The protective effect of Ca2+ on plasmic degradation of fibrinogen was incomplete with all three variants. The fibrinogen molecules in variants Homburg VII and Suhl contain covalently bound albumin. Fibrin clot structure was abnormal in case of variant Homburg VII, with finer and more branched fibers forming a less porous clot. Experimental data indicate possible effects of the molecular abnormalities on Ca2+-binding, D-E interaction and lateral association of protofibrils.