[Prevalence of Elevated Lipoprotein (a) Levels in Patients < 60 Years of Age with Retinal Vein Occlusion]. / Prävalenz erhöhter Lipoprotein(a)-Spiegel bei unter 60-jährigen Patienten mit venösen retinalen Gefäßverschlüssen.

BACKGROUND: The potential impact of elevated Lipoprotein (a) [Lp(a)] levels on retinal venous occlusive (RVO) diseases with regard to age and various risk factors has not been studied extensively. PATIENTS AND METHODS: In a retrospective case-control study, thrombophilia data of 106 young patients (< 60 years at the time of the RVO or a previous thromboembolic event) with RVO and 76 healthy subjects were evaluated. RESULTS: Elevated Lp(a) plasma levels were significantly more prevalent among RVO patients (29.2 %) than among controls (9.2 %; p = 0.0009). Lp(a) levels were found to be significantly (p = 0.012) different between patients and controls. Moreover, we found that an unusual personal or family history of thromboembolism was a strong predictor of elevated Lp(a) (p = 0.03). We observed a significant correlation between elevated Lp(a) and other coagulation disorders (p = 0.005). Multivariate analysis showed that elevated lipoprotein(a) levels (OR: 3.5; p = 0.003) were an independent risk factor for the development of RVO. CONCLUSIONS: Elevated plasma levels of Lp(a) are associated with the development of RVO. Selective screening of young patients and subjects with a personal or family history of thromboembolism may be helpful in identifying RVO patients with elevated Lp(a).

Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH).

BACKGROUND: Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients. OBJECTIVES: To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. METHODS: A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. RESULTS: A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. CONCLUSIONS: The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs.

Haemophilia patients' unmet needs and their expectations of the new extended half-life factor concentrates.

INTRODUCTION: National Member Organisations (NMO) of persons with haemophilia (PWH) from the DACH Region (D = Germany, A = Austria, CH = Switzerland) were interested to better understand PWH's expectations and concerns of extended half-life (EHL) factor concentrates (FC) before availability in these countries. METHODS: Based on an expert meeting and focus groups conducted across Germany a survey for haemophilia patients and their parents was developed and was sent out to 2,644 PWH. RESULTS: One thousand and seven questionnaires were sent back (38.1%); 743 adults and 262 parents. Most patients had haemophilia A (84.5%), were severely affected (73.7%), received prophylaxis (57%) and used recombinant FC (60.2%). One-quarter did not know the correct half-life of their FC [HA/FVIII: 26%, HB/FIX: 31.1%]. Four percent were unsatisfied with their current FC, mainly with short half-life of FC and difficult manageability. They expected from new EHL products less frequent injections (55.2%), better efficacy (32.1%) and safety/no side effects (15.7%); 59.5% would be willing to switch to new products if they have a prolonged half-life and the same safety of the current FC. They wish more information about half-life (84.4%), possible side-effects (81.3%) and efficacy (77%) and wanted to receive information about new products from their haemophilia treater (76.3%) and the newsletter of their NMO (74.3%). Significant differences across countries were found. CONCLUSIONS: The representative survey could show that although PWH were generally satisfied with their current FC, the majority would be willing to switch to EHL products assuming half-life is prolonged and has the same safety of the current FC.

[Multiple thrombophilic risk markers in patients ≺65 years of age with retinal vein occlusion]. / Multiple thrombophile Risikomarker bei Patienten ≺65 Jahre mit venösen retinalen Gefäßverschlüssen.

BACKGROUND: The potential impact of multiple thrombophilic defects on retinal venous occlusive (RVO) diseases with regard to age and various risk factors has not been studied extensively. MATERIALS AND METHODS: In a retrospective, multicenter study, thrombophilia data of 128 patients <65 years of age with RVO and 110 healthy subjects were evaluated. The main measure outcome was the prevalence of multiple thrombophilic disorders. RESULTS: Multiple thrombophilic defects were significantly more prevalent among RVO patients (18.0%) than among controls (1.8%; P < 0.0001). We identified factor VIII elevation, elevated lipoprotein(a) plasma levels and resistance to activated protein C as the most prevalent combined disorders. Factor XII deficiency and prothrombin mutation G20210A were found to be isolated thrombophilic risk factors. Multiple thrombophilic defects were significantly associated with RVO recurrence (P = 0.008). CONCLUSION: Multiple thrombophilic disorders are associated with the development of RVO among patients younger than 65 years of age. Moreover, our results suggest that patients with RVO associated with underlying combined thrombophilic defects are at increased risk for RVO recurrence. Further studies are required to analyze whether the diagnosis of combined thrombophilic defects among RVO patients could be a predictor for RVO recurrence.

Adherence to prophylactic treatment in patients with haemophilia in Germany.

INTRODUCTION: Adherence to prophylactic treatment in haemophilia is important for patient outcome. AIM: This study analysed the influence of potential impact factors on adherence assessed through the application of the German translation of the VERITAS-Pro questionnaire. METHODS: All members of the German haemophilia patient organisation (DHG) who suffer from severe or moderate haemophilia and are on continuous prophylactic treatment were asked to complete the VERITAS-Pro questionnaire. Further questions were added regarding the patients' age, severity of haemophilia, type A or B, frequency of prophylaxis, pain level, factor application self or non-self and co-morbidities. RESULTS: Responses of 397 patients on continuous prophylactic treatment, 0-80 years old, were analysed according to several age groups: 0-14, 15-19, 20-59 (20-29 and 30-39) and ≥60 years of age. The mean total VERITAS-Pro score for the whole sample was 36.7 ± 11.7 (range of 24-86). The scores were significantly higher, indicating the poorest adherence, in patients between 20 and 59 years of age (41.1 ± 11.7) compared with the other age groups (30.0-35.7). Adherence to treatment was highest in patients between 0 and 14 years of age in all subscales of the VERITAS-Pro. The following potential risk factors for non-adherence were evaluated in all age groups: organisation suffering (care by a haemophilia centre), severity and type of haemophilia, factor concentrate administration and the presence of co-morbidities. CONCLUSION: The identification of significant differences between age groups in special subscales of adherence and impact factors offers tailored starting points for improvements of adherence to prophylactic treatment.

Prospective evaluation of treatment regimens, efficacy and safety of a recombinant factor VIII concentrate in haemophilia A: the German EffeKt study.

INTRODUCTION: Collecting clinical data under routine conditions remains important to monitor continuously efficacy and tolerability of an established product. AIM: This prospective observational study aimed at evaluating efficacy and tolerability of full-length sucrose-formulated recombinant FVIII (rFVIII-FS; KOGENATE(®) Bayer/KOGENATE(®) FS) in routine use and analysing concomitant diseases and medication. METHODS: Haemophilia A patients treated with rFVIII-FS were followed up for 24 or 36 months. Efficacy, tolerability, concomitant medication and diseases were assessed at yearly intervals. RESULTS: Two hundred and twenty-one documented patients were mainly pretreated, predominantly with prophylaxis (74%). On study, 54 (31%) patients in the efficacy set (n = 174) documented regular prophylaxis, 91 patients (52.3%) failed to document their prescribed prophylactic infusions, 25 (14.4%) received on-demand treatment and four patients (2%) inhibitor adapted therapy. Patients on regular prophylaxis reported 8.4% of infusions for bleeding treatment and on-demand patients reported 55.3%. Young patients experienced mainly trauma-related bleedings and older patients reported spontaneous bleedings. Joint status was good overall. Median annual spontaneous joint bleeding rate in all groups was zero. A total of 79.0% of all bleedings were successfully treated with one or two infusions. Degenerative arthropathy and arterial hypertension were the most prominent concomitant diseases. Eighty-seven patients (40.5%) took at least one concomitant drug on study, mostly drugs for pain treatment related to haemophilic arthropathy. Two patients presented with positive inhibitor titres on study, one of them was a previously untreated patient and the other had a positive inhibitor history. CONCLUSION: This study corroborates the tolerability and efficacy profile of rFVIII-FS.

Screening for lupus anticoagulants in patients treated with vitamin K antagonists.

INTRODUCTION: The dRVVT test for detecting lupus anticoagulants (LA) is difficult to interpret when patients are treated with vitamin K antagonists (VKA). METHODS: We performed LA testing in 33 VKA-treated patients with definite antiphospholipid syndrome (APS) and compared the results with 100 controls subjects not receiving VKA and 110 APL-negative patients anticoagulated for reasons other than APS. RESULTS: Compared with the dRVVT ratio before the initiation of VKA therapy, a higher cutoff value, defined as the 99th percentile, was established for VKA-treated patients with INR values between 2.0 and 3.5. A dRVVT ratio of >1.7 yielded a sensitivity of 81.3%, specificity of 99.1%, and positive and negative predictive values of 98.7% and 85.8%, respectively, for detecting LA. Cohen's kappa coefficient indicated good agreement for the dRVVT ratio obtained from testing with and without VKA treatment (κ = 0.813; 95% CI: 0.773-0.853), which was higher (κ = 0.941; 95% CI: 0.917-0.965) when the LA diagnosis was based on the results of both the dRVVT and a second test system (i.e., Mixcon-LA assay). CONCLUSIONS: Lupus anticoagulants testing in VKA-treated patients with APS according to current guidelines appears to be possible for the majority of patients without discontinuing anticoagulant therapy.

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 µg kg(-1) ) or s.c. (50-3000 µg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h µg mL(-1) and a maximum mean concentration of 247 µg mL(-1) was measured at the highest dose. CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

Rare bleeding disorders are associated with depression and anxiety.

Thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenia (ITP) and acquired haemophilia are very rare haemorrhagic disorders (1) associated with surgery, hospitalization (2) and death being reported (3). Despite the rapid development of interventional techniques, therapeutic options for patients with these illnesses remain limited. We suppose that depression and anxiety disorders appear more frequently than in the normal population in patients with rare haemorrhagic disorders.

[Life with haemophilia. The patient's perspective of ageing]. / Leben mit Hämophilie. Erwartungen im Alter aus Patientensicht.

Patients with haemophilia are growing older and may be faced with age-dependent co-morbidities. To evaluate the impact of growing age in patients with haemophilia, a questionaire was sent to members of German patients' organisations DHG and IGH with focus on medical care and psychosocial questions. This questionnaire was answered by 466 individuals (aged 50 years, 21-85 years), predominantly suffering from severe haemophilia. The majority of individuals considered the question of substitution of factor concentrates in case of bleeding as most important. Concerns were expressed regarding the financial situation and lack of medical care in higher age. The results provide an insight into issues of growing age from the patient's perspective.

[Incidence of thromboembolic events after major operations in patients with haemophilia]. / Untersuchung zum postoperativen Verlauf bei Patienten mit Hämophilie.

UNLABELLED: Thromboembolic complications may occur in patients with major operations even after routine thromboprophylaxis with low-molecular-weight-heparin. In this retrospective, single center survey the post-operative course of patients with haemophilia was investigated. PATIENTS, METHODS: Overall, the postoperative course in 85 patients with haemophilia A and B (median age: 43 years, 18-73 years) and 139 surgical procedures was analyzed. The surgical procedures mainly consist of major orthopedic surgery (58 total knee replacement, 15 hip replacement, 17 other major orthopedic surgery, 15 minor orthopedic procedures). Additional surgical procedures were abdominal-surgical (18), urological (8), neurosurgical (5). RESULTS: During the post-operative observation period a small number of wound healing complications occurred (4%). None of the patients developed symptomatic deep vein thrombosis or lung embolism. CONCLUSION: There seems to a decreased risk of postoperative thromboembolism in patients with haemophilia.

[Inhibitor development after changing FVIII/IX products in patients with haemophilia]. / Hemmkörperentwicklung bei Hämophilie-Patienten nach Präparatewechsel. Steigt das Risiko beim Präparatewechsel an?

UNLABELLED: The retrospective observational study surveys the relationship between development of inhibitors in the treatment of haemophilia patients and risk factors such as changing FVIII products. A total of 119 patients were included in this study, 198 changes of FVIII products were evaluated. RESULTS: During the observation period of 12 months none of the patients developed an inhibitor, which was temporally associated with a change of FVIII products. A frequent change of FVIII products didn't lead to an increase in inhibitor risk. The change between plasmatic and recombinant preparations could not be confirmed as a risk factor. Furthermore, no correlation between treatment regimens, severity, patient age and comorbidities of the patients could be found.

von Willebrand's disease: a report from a meeting in the Åland islands.

von Willebrand's disease (VWD) is probably the most common bleeding disorder, with some studies indicating that up to 1% of the population may have the condition. Over recent years interest in VWD has fallen compared to that of haemophilia, partly the result of focus on blood-borne diseases such as HIV and hepatitis. Now the time has come to revisit VWD, and in view of this some 60 international physicians with clinical and scientific interest in VWD met over 4 days in 2010 in the Åland islands to discuss state-of-the-art issues in the disease. The Åland islands are where Erik von Willebrand had first observed a bleeding disorder in a number of members of a family from Föglö, and 2010 was also the 140th anniversary of his birth. This report summarizes the main papers presented at the symposium; topics ranged from genetics and biochemistry through to classification of VWD, pharmacokinetics and laboratory assays used in the diagnosis of the disease, inhibitors, treatment guidelines in different age groups including the elderly who often have comorbid conditions that present challenges, and prophylaxis. Other topics included managing surgeries in patients with VWD and the role of FVIII in VWF replacement, a controversial subject.

[Massive subretinal hemorrhage and anticoagulants. An unfortunate combination?]. / Submakuläre Massenblutung und Gerinnungshemmer. Eine unglückliche Kombination?

Exudative age-related macular degeneration (ARMD) is one of the conditions which has been shown to be associated with a risk of massive subretinal hemorrhage. Patients with thick submacular hemorrhage complicating ARMD typically have a poor visual prognosis. Antiplatelet therapy with aspirin, clopidogrel or ticlopidine has significant benefits in the secondary prevention of fatal and non-fatal coronary and cerebrovascular events. Anticoagulation is frequently used in this elderly age group for a variety of other comorbidities including prosthetic heart valves, atrial fibrillation, ischemic heart disease, cerebrovascular disease and venous thromboembolism. However, it is a well established observation that the longer patients remain on anticoagulant therapy, the higher the cumulative risk of bleeding. Over the past years, there has been a rapidly growing body of literature concerning the risk of hemorrhagic ocular complications with ophthalmic surgery in patients receiving anticoagulant therapy. By contrast, there are still little data on the relationship between anticoagulation or antiplatelet therapy and spontaneous ocular hemorrhages and only few reports have focused on patients with ARMD. Just recently, several authors reported a strong association of anticoagulants and antiplatelet agents with the development of large subretinal hemorrhages in ARMD patients. Moreover, arterial hypertension is a high risk factor for large subretinal hemorrhages in ARMD patients receiving anticoagulants or antiplatelet agents. Physicians should be aware of an increased risk of extensive subretinal hemorrhage in ARMD patients when deciding on the initiation and duration of anticoagulant and antiplatelet therapy.

Mortality and inherited thrombophilia: results from the European Prospective Cohort on Thrombophilia.

BACKGROUND: Data on the survival of individuals with hereditary thrombophilia are rare and only come from retrospective studies. OBJECTIVE: The aim of the present study was to assess mortality in individuals with known thrombophilia with and without a history of thrombosis in comparison to a control group. PATIENTS/METHODS: The European Prospective Cohort on Thrombophilia (EPCOT) study is a prospective, multi-center observational study performed to assess the risk of thrombosis in persons with inherited thrombophilia. In an extension of the present study, the vital status was assessed in 1240 individuals with thrombophilia (mean age 40.9 years, 59% women, 196 with antithrombin, 341 with protein C, 276 with protein S-deficiency, 330 with factor (F)V Leiden and 97 with combined defects, and 62% with a history of venous thrombosis [VT]) and 875 controls (mean age 42.5 years, 48% women, 7% with a history of VT). RESULTS: Seventy-two individuals with thrombophilia and 45 controls died during follow-up. The risk of death, adjusted for gender, thrombosis history and center, was not associated with thrombophilia (hazard ratio [HR] thrombophilia individuals vs. controls: 1.09, 95% confidence interval [CI] 0.66-1.78). When individuals with thrombophilia were evaluated separately, a history of thrombosis was not associated with mortality: the risk of death after adjustment for gender, anticoagulation and center was HR 0.79 (95% CI, 0.41-1.54). CONCLUSIONS: No increased risk of death in individuals with thrombophilia, not even in those with a history of thrombosis, was observed.

[Does FVIII-activity increase with age in patients with haemophilia A and carriers of haemophilia A?]. / Hämophilie-A-Patienten und Konduktorinnen für Hämophilie A. Steigt die FVIII-Aktivität mit dem Lebensalter?

UNLABELLED: The retrospective cohort study surveys the influence of age, co-morbidity and laboratory values on FVIII-activity (FVIII:C) in patients with haemophilia A with (mild n = 48, moderate n = 10, severe n = 7 and carriers n = 23). Median observation was 19 years for patients with haemophilia A and 9,5 years for carriers. RESULTS: FVIII:C levels collected from patients with mild haemophilia A displayed a significant median increase of 6.5% with proceeding age (p = 0.0013). Patients with moderate haemophilia A (and carriers of haemophilia A) showed a non significant median increase of 1.05% (carriers 8%). Eight patients showed FVIII:C levels at last blood withdrawal that indicated a change of severity from moderate to mild haemophilia A. A significant correlation was found between FVIII:C and VWF:RCo (p = 0.0203) and AFP (p < 0.0005). The correlation between FVIII:C and triglycerides and LDH was significant negative (p < 0.0005). No significant correlation could be found for FVIII:C and co-morbidity, fibrinogen, cholesterol and VWF:Ag.

Patients with isolated prolonged in vitro bleeding time. Clinical symptoms.

UNLABELLED: In patients with isolated prolonged in vitro bleeding time there is no standardised treatment concept. With this study we characterized the extent of bleeding symptoms. PATIENTS, METHODS: All diagnoses known to cause prolonged in vitro bleeding time (PFA-100) (epinephrine-cartridge >160 s, ADP-cartridge > 120 s) have been excluded, such as platelet function disorders, effects of medications, nutrition or von Willebrand disease. 75 patients (77%, n = 58 women; 23%, n = 17 men, median age 46 (16-81) years were included. All bleeding symptoms have been stored in a databank with help of a comprehensive questionnaire. RESULTS: 78% (n = 54) of all patients reported of having had an operation, 69.8% (n = 37) of them described postoperative bleedings (p = 0.0373). 13.5% (n = 5) of the 54 could remember having been randomly treated by the administration of a transfusion and only 2.7% (n = 1) were treated by substitution of von Willebrand factor. 71% (n = 51) patients indicated haematoma (p = 0.8116). About 33.8% (n = 24) patients had gum bleeding and 40.8% (n = 29, p = 0.7808) patients reported bleeding after the dentist. 41.4% (n = 29) patients suffered under frequent epistaxis (p = 0.0212). There was no correlation between prolonged epinephrine bleeding time to VWF:Ag (rho = 0.16) nor to VWF:RCo (rho = 0.12) nor between prolonged epinephrine and ADP bleeding time (rho = 0.01) nor to ROTEM® analysis. CONCLUSION: Patients with isolated prolonged PFA are mainly women and can be affected by all kinds of bleedings while haematoma is the main symptom. VWD might not be causal.

Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa).

BACKGROUND: Recombinant activated factor VIIa (rFVIIa) is used to treat bleeds in hemophilia patients with inhibitors. A subcutaneous formulation could potentially improve its half-life and make it suitable for prophylactic treatment. OBJECTIVES: A study was conducted to determine the safety of subcutaneously administered rFVIIa in patients with hemophilia and the pharmacokinetic profile (including bioavailability). PATIENTS/METHODS: This was a multicenter, open-label, cross-over comparison of single doses of intravenous rFVIIa 90µgkg(-1) and a new formulation of rFVIIa for subcutaneous injection at dose levels of 45, 90, 180, 270 and 360µgkg(-1) . Sixty subjects (12 per dose cohort) with hemophilia A or B were enrolled. RESULTS: Subcutaneously administered rFVIIa showed lower mean peak plasma concentrations and prolonged FVII activity (C(max) , 0.44-5.16IU mL(-1) [across doses]; t(1/2) , 12.4h; t(max) , 5.6h) compared with intravenously administered rFVIIa (C(max) , 51.7IUmL(-1) ; t(1/2) , 2.7h; t(max) , <10min). The absolute bioavailability of subcutaneous rFVIIa ranged from 21.1 to 30.1% across dose levels. Dose proportionality was observed within a 2-fold dose increase but not across the full dose range. No thromboembolic events, drug-related serious adverse events, severe injection-site reactions or neutralizing antibodies were reported (primary endpoint). Mild and moderate injection-site reactions were more frequent with subcutaneous than with intravenous injections. CONCLUSION: This phase I clinical trial did not identify safety concerns of prolonged exposure to rFVIIa administered subcutaneously in single doses to hemophilia patients.