Cardiovascular events and atherogenic lipid profile in chronic myeloid leukemia patients treated with nilotinib versus imatinib.

OBJECTIVES: The aim of this study was to assess cardiotoxicity and potential adverse effects related to lipid metabolism during treatment with tyrosine kinase inhibitors (TKIs) imatinib and nilotinib in patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: Eighty-two consecutive patients with CML, who received nilotinib and/or imatinib in a single haemato-oncological Slovak center between years 2002-2018 were evaluated in a retrospective study. The mean age was 55.8 years (range 22-77 years). Median of follow-up was 61.3 months. RESULTS: A significantly higher incidence of dyslipidemia, significantly higher levels of potential risk markers of cardiovascular disease small dense LDL cholesterol (sdLDL-CH) and a significant increase in total cholesterol were found in the patients during treatment with nilotinib in comparison to imatinib. Dyslipidemia led to drug therapy in 22 % of the patients in the nilotinib group. Fourteen percent of the patients in the nilotinib group had one or more cardiovascular events, including peripheral artery disease (10 %), myocardial infarction (4 %) and stroke (4 %). CONCLUSION: A higher risk of cardiovascular events and atherogenic dyslipidemia were associated with nilotinib therapy. Patients treated with TKI, especially nilotinib, require an early modification of cardiovascular risk factors and a careful cardiologic surveillance so that antileukemic therapy with this highly effective agent could continue (Tab. 4, Fig. 3, Ref. 32). Text in PDF www.elis.sk Keywords: tyrosine kinase inhibitors, cardiovascular events, dyslipidemia, small dense LDL-cholesterol, nilotinib, imatinib.

The use of granulocyte colony stimulating factor after autologous hematopoietic stem cell transplantation.

Restrospective study to evaluate the efficacy of early vs. delayed initiation of G-CSF after autologous hematopoietic stem cell transplantation (AHSCT) in patients with lymphoid malignancies. BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is commonly used after AHSCT to accelerate stem cell engraftment to minimize the morbidity and mortality associated with prolonged neutropenia. However, there is no consensus on the optimal timing of G-CSF after HSCT. METHODS: A total of 117 patients with lymphoid malignancies who underwent AHSCT were included. All patients received G-CSF (filgrastim 5 µg/kg s.c.) daily after AHSCT (43 patients on day 6-8 and 74 patients on day 3 or 4). All patients received standard conditioning regimen for the underlying disease, and standard supportive treatment, including treatment of febrile neutropenia. RESULTS: The incidence of severe neutropenia was 81 % vs 17 %, and very severe neutropenia 61 % vs 4 % in the delayed and early G-CSF groups, respectively (p < 0.0001). The rate of fungal infection was higher in the group of patients who received delayed G-CSF (p < 0.005). CONCLUSION: An early administration of G-CSF after AHSCT (on day 3 or 4) accelerates neutophil engraftment; decreases the incidence of severe neutropenia and the risk of infectious complications (especially fungal infections) (Tab. 1, Fig. 3, Ref. 22).

Continuous infusion of coagulation factor concentrates during intensive treatment.

In clinical management of bleeds and surgical procedures in patients suffering from bleeding disorders either repetitive bolus injections (BI) or continuous infusion (CI) can be used for coagulation factor replacement. Continuous infusion seems to be an attractive route of administration and may be considered if replacement therapy is required for more than 3 days. The strongest argument favouring continuous infusion is its superiority in providing the patient with a safe and constant level of the deficient coagulation factor by balancing input with clearance. Furthermore, several studies have shown that coagulation factor consumption may be reduced by CI compared to repetitive bolus injections (BI) since unnecessary peaks of factor level are avoided. Concerns have been raised whether continuous infusion of coagulation concentrates is associated with an increased risk of developing inhibitors. However, available data have so far not shown an increased risk for inhibitor development in severe haemophilia patients with more than 50 exposure days of coagulation factor concentrates. Further, previously reported complications when using CI such as phlebitis at the infusion site and pump failure are nowadays very seldom seen when small amounts of heparin are added to the infusion bag, and increased quality of the pumps are available. Over the last decades, numerous reports have confirmed CI to be a safe and effective mode of coagulation factor replacement even in the most challenging surgical procedures, such as total joint arthroplasties.

Emergency care of patients receiving non-vitamin K antagonist oral anticoagulants.

Non-vitamin K antagonist oral anticoagulants (NOACs), which inhibit thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban, edoxaban) have been introduced in several clinical indications. Although NOACs have a favourable benefit-risk profile and can be used without routine laboratory monitoring, they are associated-as any anticoagulant-with a risk of bleeding. In addition, treatment may need to be interrupted in patients who need surgery or other procedures. The objective of this article, developed by a multidisciplinary panel of experts in thrombosis and haemostasis, is to provide an update on the management of NOAC-treated patients who experience a bleeding episode or require an urgent procedure. Recent advances in the development of targeted reversal agents are expected to help streamline the management of NOAC-treated patients in whom rapid reversal of anticoagulation is required.

Autologous hematopoietic stem cell transplantation for acute myeloid leukemia - single center experience.

We aimed to determine the effect of autologous hematopoietic stem cell transplantation (auto-HSCT) on acute myeloid leukemia (AML) patients as a valid alternative therapeutic option for patients without HLA-compatible donor. This retrospective single center study included 79 patients with AML older than 18 years. In this report, we describe the patient characteristics, engraftment, toxicity of treatment, complications, overall survival, and relapse incidence of 79 patients treated chemotherapy and followed by auto-HSCT. The descriptive statistics was used, and the method of Kaplan and Meier was applied to calculate the actuarial rate of overall survival. The patients achieved an absolute neutrophile count (ANC) of ≥ 0.5 x109/l in between 10 to 40 days; median was 14 days after auto-HSCT. The patients achieved platelet count ≥ 20 x109/l in between 10 to 209 days; median was 19 days after auto-HSCT. Hundred-day mortality after autologous transplant was 6.57% (5/76). The relapse rate was 39.5% (32 patients) and 7 patients (8.6%) were lost from follow-up. On the date of evaluation (April 30, 2016), 48 patients (60.8%) were alive, including 7 (8.6%) patients who are lost from follow-up (not responding to check-up request). The 5-year overall survival (OS) was 60.8%; median overall survival was not reached. The present clinical study has demonstrated safety and efficacy of myeloablative chemotherapy followed by auto-HSCT in the treatment of AML in first remission.

Women with congenital factor VII deficiency: clinical phenotype and treatment options from two international studies.

INTRODUCTION: A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. AIM: Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. METHODS: A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. RESULTS: In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 µg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 µg kg(-1) (divided as three doses). CONCLUSION: Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies.

Graft-versus-host disease management.

Graft-versus-host disease (GVHD) remains a major problem of allogeneic hematopoietic-stem cell transplantation (HSCT) and an obstacle for successful outcome. Clinically significant acute GVHD (grade II or higher) developed in 20 to 65 percent of the patients. Death due to this complication accounts for approximately 50 percent of the deaths that are not due to a relapse of the neoplasm. Up to 70 % of patients who survive beyond day 100 develop chronic GVHD and it is the leading cause of nonrelapse mortality more than 2 years after allogeneic HSCT. In addition, chronic GVHD is associated with decreased quality of life, impaired functional status, and ongoing need for immunosuppressive medications. The incidence of chronic GVHD is increasing because of expansion of the donor population beyond HLA-identical siblings, older recipient age, use of peripheral blood cells as the graft source, and infusion of donor lymphocytes for treatment of recurrent malignancy after HSCT. With the current rush in new findings related to GVHD, we see a significant advancement in its management. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of GVHD, as access to the most sophisticated advances may vary depending on local circumstances (Tab. 4, Fig. 1, Ref. 51).

Collection of peripheral hematopoietic stem/progenitor cells.

OBJECTIVES: Several variables possibly affecting collection of peripheral hematopoietic stem/progenitor cells (PBSC) were evaluated: type of apheresis machine (Amicus version 2.5, Baxter vs Cobe Spectra version 7.0, Terumo BCT), venous access (peripheral vein vs central venous catheter, i.g. CVC), and apheresis regimen (standard vs large volume leukapheresis, i.g. SVL vs LVL) with the objective to increase collection efficacy at the site. BACKGROUND: Peripheral blood represents the currently preferred source of hematopoietic stem/progenitor cells (HSCs) for transplantation. METHODS: Data regarding 169 collection procedures performed in healthy donors and patients between January 2008 and December 2011 at the Clinics of Haematology and Transfusiology in St Cyril and Method Hospital in Bratislava (Slovakia) were analysed. RESULTS: With Cobe Spectra apheresis machine it was possible to process larger blood volumes per procedure with higher CD34+ cell collection efficiency (p = 0.0229) and lower RBC contamination of the harvest than with Amicus (p = 0.0116). On the other hand, Amicus helped to limit PLT contamination of the harvest (p < 0.0001), thus minimizing post-procedural decrease in patient´s PLT count. The highest detected advantage of CVC usage was higher flow rate of procedure, thus processing larger blood volumes per unit of time. Interesting finding was the tendency to lower harvest PLT contamination (p = 0.054). When LVL was performed, significantly higher HSCs yields were collected, even in "poor mobilizers" when the pre-run parameters were low. CONCLUSION: Management of PBSC collection requires a particular approach in each subject. Institutionally and individually optimized collection may help to improve the transplantation outcome and decrease the financial costs (Tab. 8, Ref. 15).

Longitudinal evaluation of markers of hemostasis in pregnancy.

OBJECTIVE: The aim of this study was to establish the physiologic changes in hemostasis during pregnancy and to find the association between the factor V Leiden mutation and adverse pregnancy outcome. METHODS: We investigated blood samples of 148 pregnant women during each trimester of pregnancy. We measured their serum concentrations of factors I, II, V, VII, VIII, IX, X, XI, XII, D-dimers, prothrombin time, INR, aPTT, activity of protein C and S, antithrombin III and platelet count. The pregnancy outcome of women with factor V Leiden mutation was compared to those without congenital thrombophilia. RESULTS: Prothrombin time, INR and aPTT were significantly shorter. We found significantly higher plasma concentrations of fibrinogen and d-dimers and higher levels of activity of factor VII and X in the third trimester. No significant difference was found in protein C and antithrombin III activity. The protein S activity was lower in the second trimester and it increased in the third trimester. Although most of the clotting factors were rising during the pregnancy, there was no evidence of fibrinolytic overactivation. In our study, the carriership of factor V Leiden mutation did not affect the incidence of preeclampsia, eclampsia, intrauterine fetal death and venous thromboembolism. Placental abruption was rare. CONCLUSION: Hemostatic changes in pregnancy are significant and essential, and have the potential to cause adverse pregnancy outcome. In addition, hypercoagulable state during pregnancy is considered to be physiological (Tab. 4, Ref. 36).

[Pomalidomide in the treatment of relapsed and refractory multiple myeloma]. / Pomalidomid v liecbe relabujúceho a refraktérneho mnohopocetného myelómu.

Despite improvements in multiple myeloma therapy, the vast majority of patients continue to suffer relapses. Unfortunately, many patients event. develop disease that is refractory to lenalidomide and bortezomib and have few treatment options. Pomalidomide is a potent second-generation immunomodulatory agent with direct antiproliferative, pro-apoptotic, and antiangiogenic effects, as well as modulatory effects on bone resorption and on the immune system. Pomalidomide exhibited more potent anti-myeloma activity compared with thalidomide and lenalidomide. The optimal starting dose of pomalidomide is 4 mg given orally on days 1-21 of each 28-day cycle and combination with dexamethasone produces synergistic effects. In clinical trials, pomalidomide plus low-dose dexamethasone has shown better responses, progression-free and overall survival than high-dose dexamethasone or pomalidomide alone. Pomalidomide has limited cross-resistance with lenalidomide, and the overall response rates of pomalidomide in lenalidomide/bortezomib dual-refractory patients ranged from 26 to 31%. The most common grade 3 or 4 adverse events are hematologic, consisting of neutropenia, thrombocytopenia and anemia. Pomalidomide was approved by the FDA and the EMA in patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on their last therapy. We review pomalidomide mechanism of action, clinical trials in relapsed and refractory patients, and novel pomalidomide-based combinations.

Neonatal bleeding in haemophilia: a European cohort study.

Birth is the first haemostatic challenge for a child with haemophilia. Our aim was to examine the association between perinatal risk factors and major neonatal bleeding in infants with haemophilia. This observational cohort study in 12 European haemophilia treatment centres (HTC) incorporated 508 children with haemophilia A or B, born between 1990 and 2008. Risk factors for bleeding were analysed by univariate analysis. Head bleeds occurred in 18 (3·5%) children within the first 28 d of life, including three intraparenchymal bleeds, one subdural haematoma and 14 cephalohaematomas. Intra-cranial bleeds were associated with long-term neurological sequelae in two (0·4%) cases; no deaths occurred. Assisted delivery (forceps/vacuum) was the only risk factor for neonatal head bleeding [Odds Ratio (OR) 8·84: 95% confidence interval (CI) 3·05-25·61]. Mild haemophilia and maternal awareness of her haemophilia carrier status seemed to be protective (OR 0·24; 95%CI 0·05-1·05 and OR 0·34; 95%CI 0·10-1·21, respectively), but due to the low number of events this was not statistically significant. We found no association between neonatal head bleeding and country, maternal age, parity, gestational age or presence of HTC. Maternal awareness of carrier status protected against assisted delivery (unadjusted OR 0·37; 95%CI 0·15-0·90; adjusted OR 0·47 (95%CI 0·18-1·21).

Recommendations for assessment, monitoring and follow-up of patients with haemophilia.

Over the last few decades, clinical follow-up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow-up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources.

Continuous infusion in haemophilia: current practice in Europe.

Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement therapy in haemophilia. Recently, concerns have been raised regarding association of CI with the development of inhibitors. The aim of this study was to gain information on the current practices in Europe regarding CI and the true inhibitor incidence after this mode of therapy. In a cross sectional study performed in 22 Comprehensive Care Centres (CCCs), we evaluated CI techniques, treatment protocols, efficacy, safety and complications of CI including inhibitors. Thirteen (59%) CCCs reported a total of 1079 CI treatments, given peri-operatively or for major bleeds, in 742 patients. Most centres used 'adjusted dose' CI aimed at median target FVIII level of 0.8 IU mL(-1). CI was haemostatically very effective with a low incidence of complications: median incidence of postoperative bleeding was 1.8%, six centres observed phlebitis in 2-11% of CI treatments. Only nine (1.2%) patients developed inhibitors (0.45% of 659 severe and 7.2% of 83 mild haemophilia patients). Additional analysis of inhibitor patients revealed several confounding factors (low number of prior FVIII exposure days, high steady-state factor levels during CI, high-risk genotype). In this unprecedentedly large cohort, CI treatment appears to be an effective and safe treatment that does not increase the risk of inhibitor development in patients with severe haemophilia. Thus, previous small case series reports suggesting that CI may increase inhibitors cannot be confirmed. Inhibitor risk in mild haemophilia could not be evaluated as the influence of other, potentially confounding, risk factors could not be excluded.

Cardiovascular complications among hematopoietic cell transplantation survivors - the role of cardiomarkers.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for numerous malignant and nonmalignant diseases. The number of survivors and length of follow-up after successful HSCT is continually increasing. HSCT can induce damage of various organs and tissues - from minimal potentially progressive subclinical changes to life-threatening conditions. The aim of this thesis was to assess the prognostic value of high sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing and early identification of patients at high risk of a cardiac event after allogeneic HSCT. PATIENTS AND METHODS: Sixty-three patients with the median age of 37 years at the time of allogeneic HSCT for hematologic diseases were studied. Cardiac bio-markers were serially measured before conditioning regimen and at days 1, 14 and 30 after HSCT. Cardiac systolic and diastolic functions were assessed before the conditioning regimen and 1 month after HSCT by echocardiography. RESULTS: The differences in plasma NT-proBNP and hs-cTnT concentrations during the 30 days following HSCT were statistically significant (P < 0.001 vs. P = 0.02). Seven of 63 patients (11.1 %) developed a cardiac event defined as cardiovascular dys-rhythmias, pericarditis with cardiac tamponade and heart failure. By multivariate analysis, the strongest prognostic factor of cardiac event was an increased level of hs-cTnT and NT-proBNP persisted for a period of 14 days after HSCT (P < 0.0001). The area under the curve from hs-cTnT testing plus NT-proBNP testing together (AUC = 0.95) was superior to each dia-gnostic modality alone. CONCLUSION: Measurements of plasma NT-proBNP and hs-cTnT concentrations might be a useful tool for identification of high-risk patients requiring further cardiological follow up. Measurement of hs-cTnT plus NT-proBNP together was superior to hs-cTnT and NT-proBNP measurements alone.

Metabolic syndrome in long-term survivors after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for numerous malignant and non-malignant diseases. The number of survivors and length of follow-up after successful HSCT is continually increasing. Hematopoietic stem cell transplantation can induce damage of various organs and tissues - from minimal potentially progressive subclinical changes to life-threatening conditions. The aim of this thesis was the evaluation of the prevalence of metabolic syndrome (MS) among survivors of allogeneic HSCT. PATIENTS AND METHODS: We analyzed 74 patients with a median age at transplant of 35 years, who had been followed for a median of 5 years (2-23 years) after allogeneic HSCT. MS was defined according to the National Cholesterol Education Programs Adult Treatment Panel III (NCEP ATP III) criteria and by the International Diabetes Federation (IDF) definition. RESULTS: The prevalence of MS among HSCT recipients was 40.5% applying the NCEP ATP III definition and 39.2% the IDF, a 2.02-fold increase compared to the general Slovak population. MS was more common in men. The most common MS features were abdominal obesity, hypertriglyceridemia and hypertension. The lowest prevalence of MS was in the age group of 20-29 years; and the highest prevalence in the age group of 60-69 years. The 10-year cumulative incidence of MS was 32.5%. The most significant risk factor for MS was total body irradiation, positive family history and age > 40 years at HSCT. Seven patients (9.45%) developed cardiovascular complications. The median 10-year general cardiovascular risk scores for males and females were found to be 13.3% and 6.68%, respectively. CONCLUSIONS: Detected increased prevalence of metabolic syndrome after allogeneic HSCT in patients surviving more than 2 years after this procedure may provide next stimulus to promote longer follow-up studies and to design of interventions to prevent late effects among survivors of serious hematologic diseases.

Special lectures in haemophilia management.

SUMMARY: During the last two decades major advances have been achieved in the management of haemophilia. Modern approaches aimed at preventing the recurrent bleedings and their sequelae have been widely adopted. Major challenges of intensive treatment regimens employed today, such a short half life of haemophilia therapeutics with a need for frequent injections and the risk of inhibitor, encourage further development towards the production of factor concentrates with prolonged efficacy and reduced immunogenicity. Intensive research work on gene therapy aimed at ultimate cure of haemophilia by the restoration of missing factor FVIII (FVIII) and factor IX (FIX) production is ongoing. The current issues of gene therapy and mechanisms, modifying the host immune response to the FVIII and FIX transgene material and the coagulation factors expressed are the topic of the Arosenius lecture by Katherine High. Despite an extensive research on mechanisms leading to inhibitor development, the real reason of these serious complications of haemophilia therapy still remains unclear. Alessandro Gringeri will discuss the immunogenicity of plasma derived FVIII (pd FVIII) and recombinant FVIII (rFVIII) concentrates as one of potential, treatment related, and probably 'modifiable' risk factors for inhibitor development. The SIPPET study--a new prospective, randomised study aimed to reveal real incidence of inhibitors in patients treated with either pdFVIII or rFVIII will be presented.

Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report.

SUMMARY: The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors--perceived by the immune system as danger signals--which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB). Taken together, this information highlights the lack of robust data concerning the influence of several non-genetic risk factors on inhibitor development, and an urgent need for prospective, well-conducted studies that adhere to recommendations made by the European Medicines Agency (EMEA) for studying inhibitors. Based on current literature, the EHTSB formulated consensus recommendations. It is desirable to minimize intensive treatment wherever possible, given the clinical situation. Prophylaxis should be offered to all children, although we still need to determine optimal dosing with respect to inhibitor development, and age for starting treatment. Vaccinations should be given subcutaneously and concomitant factor concentrate infusions avoided. According to the board, there is no evidence in the literature supporting suggestions that the type of concentrate influences inhibitor risk; but all patients should be monitored during their first exposures. Furthermore, there is no evidence to support an association between pregnancy-related issues, breast feeding and treatment-related factors (e.g. route of administration, or use of blood components) and inhibitor development.

Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene.

The congenital FVII deficiency (FVIID) is a rare haemorrhagic disorder with an autosomal recessive pattern of inheritance. Data on phenotype and the genotype from 717 subjects in Central Europe (six countries), Latin America (Costa Rica, Venezuela) and United States, enrolled in the Greifswald Registry of FVII Deficiency were analysed. We detected 131 different mutations in 73 homozygous, 145 compound heterozygous and 499 heterozygous subjects. Regional differences were observed in the mutation pattern and the clinical profile of the evaluated patients. Seventy-one per cent of homozygous and 50% of compound heterozygous subjects were symptomatic. The clinical manifestations of the homozygous subjects were characterized by intracranial haemorrhage (2%), gastrointestinal bleeding (17%), haemarthrosis (13%), epistaxis (58%), gum bleeding (38%), easy bruising (37%), haematoma (15%), haematuria (10%) and menorrhagia (19 of 26 females, 73%). The clinical variability and genotype-phenotype correlation was evaluated in the homozygous subjects. The pattern of bleeding symptoms among compound heterozygous patients was severe and similar to that of the homozygous patients. The large-scale analysis of 499 heterozygous subjects shows that 93 (19%) presented with spontaneous bleeding symptoms such as haemarthrosis (4%), epistaxis (54%), gum bleeding (14%), easy bruising (38%), haematoma (23%), haematuria (5%) and menorrhagia (19 of 45 females; 42%). The severe haemorrhages - intracranial and gastrointestinal - were not reported in heterozygous subjects. The clinical variability and the regional differences in the mutation pattern are discussed regarding care and treatment.

Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations.

Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80-90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10-14 days; for liver biopsy, 70-100%, 1-7 days; tonsillectomy: 90-100%, 5-11 days; indwelling venous access device insertion: 100%, 3-10 days; circumcision: 50-60%, 2-4 days; dental surgery: 30-50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better-designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.