Impact of Telemedicine Tools on Record Keeping and Compliance in Haemophilia Care.

BACKGROUND: Record keeping is integral to home treatment for haemophilia. Issues with paper diaries include questionable compliance, data validity and quality. Implementation of electronic diaries (e-diaries) in haemophilia patients could improve documentation of home treatment. AIM: This article evaluates the effects of an e-diary, Haemoassist, on recording and patient compliance with therapy. PATIENTS AND METHODS: An explorative study was used to assess the sequential use of paper diaries and e-diaries by 99 patients with severe haemophilia A or B and 1 with severe factor VII deficiency. Median age was 41 years. Information was obtained from paper records for 3 years preceding the introduction of an electronic record system and the first 6 to 12 months of Haemoassist use. Data from the 3-year period were averaged. Missing data for rounded 12 months of e-diary use were extrapolated to correspond to a full year. RESULTS: Enhancement of 23% in record delivery was observed for the period of Haemoassist use (p = 0.013). Twenty-one percent increase in patients' compliance for data reporting (from 65% 35 to 86% 22, p = 0.003) and 16% increase for documentation of bleedings (from 68 to 84% of patients, p = 0.01) were detected. Compliance to prescribed therapy of patients for the whole studied period improved by 6% (from 82% ± 29 to 88% ± 25, p = 0.05). Major advances were demonstrated predominantly in the age groups of between 13 and 20 and 21 and 40 years. CONCLUSION: e-Diaries' use enables improved recording of information about patients' home treatment and bleeding episodes. Enhanced compliance with therapy may be a further benefit.

Obesity in the global haemophilia population: prevalence, implications and expert opinions for weight management.

Overweight and obesity may carry a significant disease burden for patients with haemophilia (PWH), who experience reduced mobility due to joint inflammation, muscle dysfunction and haemophilic arthropathy. This review aimed to define the prevalence and clinical impact of overweight/obesity in the global population of PWH. A detailed literature search pertaining to overweight/obesity in haemophilia in the last 15 years (2003-2018) was conducted, followed by a meta-analysis of epidemiological data. The estimated pooled prevalence of overweight/obesity in European and North American PWH was 31%. Excess weight in PWH is associated with a decreased range in motion of joints, accelerated loss of joint mobility and increase in chronic pain. Additionally, the cumulative disease burden of obesity and haemophilia may impact the requirement for joint surgery, occurrence of perioperative complications and the prevalence of anxiety and depression that associates with chronic illness. Best practice guidelines for obesity prevention and weight management, based on multidisciplinary expert perspectives, are considered for adult and paediatric PWH. Recommendations in the haemophilia context emphasize the importance of patient education and tailoring engagement in physical activity to avoid the risk of traumatic bleeding.

Composition and dynamics of the uterine NK cell KIR repertoire in menstrual blood.

Uterine natural killer (NK) cells are abundantly present in endometrium and decidua. Their function is governed by interactions between killer cell immunoglobulin-like receptors (KIRs) and cognate human leukocyte antigen (HLA) class I ligands. These interactions have implications for reproductive success. Whereas most uterine NK cells are known to express KIRs, little information is available about KIR repertoire formation and stability over time. This is primarily due to inherent difficulties in gaining access to human uterine tissue. As endometrial immune cells are shed during menstruation, menstrual blood may serve as a source for studies of KIRs on uterine NK cells. Here, we performed a combined assessment of six inhibitory and activating KIRs on uterine NK cells from paired menstrual and peripheral blood. Menstrual blood contained a high frequency of uterine NK cells expressing KIRs. The uterine NK cell KIR repertoires were markedly different from those in peripheral blood NK cells, biased toward KIR2D-receptor expression, and formed independently of selection conferred by cognate HLA class I molecules. Moreover, uterine NKG2C+self-KIR+ NK cell expansions were detected. Finally, the distinct KIR repertoires of uterine NK cells were stable over multiple menstrual cycles. Our results provide novel insight into KIR repertoire formation on human uterine NK cells.

Neoplasm-induced bleeding in inherited, heterozygous FXIII-A deficiency.

UNLABELLED: Inherited mild factor XIII deficiency belongs to one of the most underdiagnosed bleeding disorders so far. This is, because most patients do not develop bleeding complications in daily life. Patient, methods: A man (age: 64 years) without a history of bleeding presented with painful swelling of neck, weight loss, anemia and episodic bleeding from the right tonsil necessitating tonsillectomy. Histologic and immunohistochemical evaluation revealed cytokeratin-positive epitheloid angiosarcoma. Blood coagulation status showed significantly elevated D-dimer and decreased FXIII levels (FXIII-activity 35%, FXIIIA-Ag 16-26%). Plasma mixing studies excluded neutralizing antibodies against FXIII. RESULTS: A novel heterozygous F13A1 gene nonsense mutation (p.Glu103Ter, c.307G>T) was found confirming heterozygous FXIII-A deficiency. The same mutation was detected in two further asymptomatic relatives. For further clinical management the patient was transfused with FXIII-concentrate and showed an adequate increase of FXIII ruling out FXIII deficiency to be induced by increased turnover. Despite this haemostatic management and antifibrinolytic treatment the patient had to undergo several revisions due to delayed, Hb relevant bleeding after cervical lymph nodes extirpation and resection of tonsil. Two chemotherapy cycles with paclitaxel and palliative radiotherapy of the neck area were performed, but the patient died unfortunately two months after diagnosis. CONCLUSIONS: It is a unique case showing the combination of a highly aggressive angiosarcoma and presence of inherited FXIII deficiency. It is also a rare example demonstrating the benefit of FXIII genotyping besides the expected acquired FXIII deficiency possibly due to neoplasm induced increased consumption by elevated crosslinking of fibrin fibers.

Treatment of minor severe acquired haemophilia. Is there a rationale for immunoadsorption?

OBJECTIVES: In Acquired Haemophilia (AH) autoantibodies against blood coagulation factors, mainly FVIII, inhibit the blood coagulation cascade. The clinical symptoms can vary from minor to severe life threatening bleedings. At present it is unclear if the intensity of the treatment needs to be adapted to the severity of the disease. METHODS: The clinical data and long term outcome from 20 patients suffering from minor severe AH were summarized. Bleedings requiring no blood transfusions were defined as less severe. In case of FVIII concentration <5% an immunosuppressive treatment (IT) consisting of cyclophosphamide 1-2 mg/kg BW/d and/or prednisolone 1-2 mg/kg BW/d was initiated. RESULTS: IT induced complete remission (CR) in only 40% of patients (8/20) after a mean time of 133.4 d (±90.7 d). Treatment associated severe side effects occurred in all patients. 15 patients required a factor substitution therapy due to proceeding bleedings. In 7 patients a partial remission (PR) of AH could be achieved; bleedings progressed in 5 of them and they underwent successfully second line immunoadsorption-based protocol. The inhibitor titer differed statistically significant between CR and PR with a mean of 3.7 BU vs. 16 BU. 5 patients had a fatal outcome mainly due to severe disease associated co morbidities. CONCLUSION: Immunosuppressive treatment failed in nearly a half of AH patients. Mortality was with 25% still high. The majority of patients required an intense long-term IT and developed severe treatment related side effect. Immediate start of IT did not control bleeding. In consequence, less severe AH also should be treated with a more rigorous regime because the occurrence of minors bleedings at initial presentation is not a predictive of clinical outcome. An Immunoadsorption-based protocol should be considered first line or even as a salvage strategy.

Long-term outcome of liver transplantation in HCV/HIV coinfected haemophilia patients. A single centre study of 10 patients.

UNLABELLED: The outcome and clinical features during long term follow-up of 10 haemophilia patients (haemophilia A n = 9, haemophilia B n = 1), who underwent successful orthotopic liver transplantation (OLT) due to hepatitis associated liver disease, are summarised. PATIENTS: Eight patients were HIV/HCV co-infected. Despite severe postoperative complications, which were not bleeding-associated, all patients survived OLT. RESULTS: Long-term survival was 70% after in mean 8 years follow-up. Twelve years after OLT one patient developed a cyclosporine-induced nephropathy requiring haemodialysis. HIV-HAART was initiated in all patients after OLT, and allowed a successful HCV treatment in 6 patients. Factor VIII production was sufficient in mean 72 h after OLT and remained stable at subnormal to normal FVIII levels of in median 30% (range 14-96%) also during long-term follow-up. Post-OLT spontaneous bleeding events were rare compared to pre-OLT, therefore, the performance status improved in all patients. DISCUSSION: OLT substitutes the hepatic FVIII but has no effect on the extra-hepatic endothelial FVIII production, suggesting that in case of severe tissue injury enhanced bleeding might occur. Additionally, after OLT there is no acute phase reaction of the FVIII protein. Therefore, our OLT patients received in case of a reduced FVIII activity a peri-interventional prophylactic short-term FVIII substitution in surgical and diagnostic interventions with high bleeding risk. CONCLUSION: Bleeding and wound healing disturbances were not seen.

No increased bleeding risk for oral surgery in patients with severe congenital bleeding disorders due to intense perioperative management.

PURPOSE: In order to evaluate complication rates of dentoalveolar surgery in patients with congenital bleeding disorders, a retrospective case-control study was performed. METHODS: A collective of patients with congenital bleeding disorders (n = 69), who received common oral surgery procedures in combination with intense perioperative monitoring and coagulation factor substitution at the University Hospital of Bonn between 1992 and 2011, was matched with patients without bleeding disorders by age, sex, and type of surgery. In addition to the rates of perioperative bleeding and other complications, the duration of surgery and the use of local hemostatic agents were compared between both cohorts. RESULTS: There were no significant differences between the two groups regarding the rate of postoperative bleeding (2.9 vs. 1.4%, patients with congenital bleeding disorders vs controls) and the rate of other complications (7.2 vs. 21.7%). Furthermore, no significant difference in operation time (54 min in patients with congenital bleeding disorders vs 45 min in controls) was observed. However, there was a significant difference (p < 0.001) regarding the use of local hemostatic measures, which were applied in all patients with hereditary bleeding disorders but in only one of the controls. All patients with bleeding disorders were inpatients, while all controls were treated in an outpatient setting. CONCLUSIONS: If adequate measures are taken, the complication rate following oral surgery in patients with hereditary bleeding disorders can be reduced to that of patients without bleeding disorders. However, these results are reached at significant costs due to coagulation factor replacement and inpatient treatment.

Inhibitor development and management in three non-severe haemophilia A patients with T295A variant.

Missense mutations are the most common F8 gene defects among the patients with non-severe haemophilia A. This type of mutation is typically associated with low (5%) inhibitor risk. In the present retrospective study we analysed the clinical data of 16 haemophiliacs with the T295A missense mutation treated at Bonn Haemophilia Centre. In total, three patients developed inhibitors: two patients experienced low-titer and one high-titer inhibitors. Both patients with low titer inhibitors underwent successful ITI. The third patient, at the age of 81, developed initially low-titer inhibitors (3 BU/ml) after rFVIII therapy because of knee surgery. He experienced spontaneous multiple large skin haematomas and haemarthrosis. Immunosuppressive therapy was not applicable because of the infectious origin of discitis (Th3-Th4). Immunoadsorption was performed, but the inhibitor titer increased up to 42 BU/ml nine weeks after termination. A successful treatment of discitis with antibiotics finally allowed a weekly therapy (four times) with rituximab (375 mg/m(2)). This resulted in a decrease of inhibitor titre to 0.7 BU/ml eight weeks after the fourth rituximab application. Patient had endogenous FVIII levels of 3-5%. Twelve months after rituximab therapy (after B cells recovery) he relapsed with low-titer inhibitors and therefore was treated with single rituximab dose (375 mg/m(2)) again. This resulted in his depletion of B cells, measurable endogenous FVIII levels and non measurable inhibitors. This study demonstrated T295A variant to be associated with significantly increased (3/16 patients, 17%) inhibitor development.

Deep intronic 'mutations' cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNA.

BACKGROUND: In a small group of typical hemophilia A (HA) patients no mutations in the F8 coding sequence (cDNA) could be found. In the current study, we performed a systematic screening of genetic and non-genetic parameters associated with reduced FVIII:C levels in a group of mostly mild HA (only one moderate) patients with no detectable mutations in F8 cDNA. METHODS: We determined FVIII and VWF activity and antigen levels and performed VWF-FVIII binding (VWF:FVIIIB) and VWF-collagen binding assays (VWF:CB) as well as VWF multimer analysis. VWF was completely sequenced to exclude mutations. The F8 locus, including the introns, was sequenced using overlapping long-range PCRs (LR-PCRs) combined with a next generation sequencing (NGS) approach. Moreover, the F8 mRNA was analyzed quantitatively and qualitatively by real-time PCR (qRT) and overlapping reverse transcription (RT) PCRs, respectively. RESULTS: All VWF tests were normal. The LR-PCRs demonstrated the integrity of the F8 locus. Eight unique polymorphisms were found in the patients, with two being recurrent. Furthermore, RT-PCRs analysis confirmed that two of the unique variants create detectable new cryptic splice sites in the patients that result in the introduction of intronic DNA sequences into the mRNA and create premature stop codons. CONCLUSION: By systematically excluding all possible causes of HA, we could with great certainty conclude that deep intronic mutations in F8, although rare, cause abnormal mRNA splicing, leading to mild HA.

Long term outcome of patients with acquired haemophilia--a monocentre interim analysis of 82 patients.

BACKGROUND: Acquired haemophilia (AH) is a rare condition leading to life threatening bleedings with a mortality ranging between 7.9 and 22%. Due to the low incidence of AH, randomized studies are not available, but observational studies with a long term follow up are of high interest. METHODS: Our haemophilia centre has documented since 1994 the treatment of 82 patients with AH, suffering from severe and moderate AH. Patient's clinical data, treatment schedules and long term outcomes were analyzed. RESULTS: In 73% of patients the first manifestation of AH was a severe life threatening bleeding. These patients were successfully treated via a multimodal immunomodulating regime (Bonn Protocol) with an overall response rate of 93% after a median treatment time of 16 d (95% CI: 13-18.9 d). Solid cancer, lymphoma, surgery and an adjacent autoimmune disease were the main "associated conditions" of AH (AHSAC). In patients with less severe AH, conventional immunosuppressive treatment was successful in 11 patients after a median of 3.9 months (range 1-12), 5 patients failed and were treated successfully second line via the Bonn protocol. In both treatment groups no bleeding associated fatalities occurred. Four patients required an additional treatment of acute bleedings with bypassing agents leading to fatal thrombotic events. CONCLUSION: Our data show that an optimal treatment schedule in AH should be adapted to the patient's individual risk profile considering the severity of bleeding and comorbidities. Idiopathic AH predisposes to severe AH requiring a more intensive treatment compared to AHSAC. In the latter, the so called "bystander immunological phenomena" induced by the primary disorder might have an important impact on the inhibitor development. Therefore the differentiation between idiopathic AH and AHSAC should be considered for a treatment decision.

[Lactones. 22. Synthesis and reduction of alpha-aminomethylene-delta,delta-diphenyl-delta-valerolactones]. / Lactone, 22. Mitt.: Zur Synthese und Reduktion von alpha-Aminomethylen-delta,delta-diphenyl-delta-valerolactonen.

Treatment with tris-(dimethylamino)-methane resp. formylation and reaction with piperidine transfer 1 to 5a,b, which can not be reduced to the corresponding alpha-aminomethyllactones 4a,b, in contrast to the homologue 6 and other alpha-aminomethylene-gamma- and delta-lactones. Isolation of products and gc/ms-investigations verify the reaction course: The aminomethyl moiety in alpha-position of delta,delta-diarylated delta-lactones is instable and eliminates amine to give 7 (NaCNBH3) or 9 (H2/Pt). Only cleavage of the lactone ring enables the formation of stable aminomethyl compounds (10,11). 5a shows weak parasympatholytic and no H1-antihistaminic activity at the isolated guinea-pig ileum.