Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. RESULTS: All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1 years. The mean (SD) annual treatment costs (€ per kg) were 4391€ (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383 448€ (259 085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. CONCLUSIONS: Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2 years.

Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment.

INTRODUCTION: Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life-threatening bleeding events, which are poorly understood. AIMS: To characterize alterations in haemostatic and fibrinolytic variables associated with LPI. METHODS: We enrolled 15 adult patients (8 female) and assessed the clinical ISTH/SSC-BAT bleeding score (BS). A variety of metabolic and coagulation assays, including fibrin generation test derivatives, clotting time (CT) and clot lysis time (CLT), thromboelastometry (ROTEM), and PFA-100 and Calibrated Automated Thrombogram (CAT), were used. RESULTS: All patients had mild-to-moderate renal insufficiency, and moderate bleeding tendency (BS 4) without spontaneous bleeds. Mild anaemia and thrombocytopenia occurred. Traditional clotting times were normal, but in contrast, CT in fibrin generation test, and especially ROTEM FIBTEM was abnormal. The patients showed impaired primary haemostasis in PFA, irrespective of normal von Willebrand factor activity, but together with lowered fibrinogen and FXIII. Thrombin generation (TG) was reduced in vitro, according to CAT-derived endogenous thrombin potential, but in vivo TG was enhanced in the form of circulating prothrombin fragment 1 and 2 values. Very high D-dimer and plasmin-α2-antiplasmin (PAP) complex levels coincided with shortened CLT in vitro. CONCLUSIONS: Defective primary haemostasis, coagulopathy, fibrin abnormality (FIBTEM, CT and CLT), low TG in vitro and clearly augmented fibrinolysis (PAP and D-dimer) in vivo were all detected in LPI. Altered fibrin generation and hyperfibrinolysis were associated with the metabolic and renal defect, suggesting a pathogenetic link in LPI.

Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series.

BACKGROUND: Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development. METHODS: We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch). RESULTS: We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5-135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases. CONCLUSIONS: By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.

Safety surveillance in haemophilia and allied disorders.

The introduction of clotting factor concentrates has transformed the lives of persons with inherited bleeding disorders. With the use of prophylactic treatment, it is now possible to prevent bleeding in these individuals. The early concentrates were contaminated with the HIV and hepatitis C viruses (HCV) and resulted in major morbidity and mortality in the recipients. Current products are much safer, especially in terms of infectious agents, but other adverse events such as alloantibodies (inhibitors), allergic reactions and thrombotic risks remain of concern. Approximately 30% of previously untreated patients with severe haemophilia A develop inhibitors, making this the most important issue in haemophilia care today. Recently, it was suggested that one of the most commonly used concentrates was associated with a higher inhibitor risk, but this was not supported by the evidence from all studies. Good safety surveillance systems are essential for all diseases and products but are particularly so in the group of individuals with inherited bleeding disorders treated with clotting factor concentrates who have suffered disproportionately from the adverse effects of their treatment. National and multinational systems are now in place to allow reporting of adverse events in patients with inherited bleeding disorders. All clinicians treating individuals with inherited bleeding disorders should prospectively report adverse events to treatment even if they are believed to be common and well recognized.

Inhibitor development in previously untreated patients with severe haemophilia A: a nationwide multicentre study in Finland.

INTRODUCTION: Currently the most serious treatment complication of haemophilia is the inhibitor development (ID), i.e. neutralizing antibody development. AIM: This nationwide multicentre study in Finland evaluated the incidence and risk factors of ID in previously untreated patients (PUPs) with severe haemophilia A (FVIII:C < 0.01 IU mL(-1) ). METHODS: We enrolled all PUPs (N = 62) born between June 1994 and May 2013 with at least 75 exposure days (EDs) to screen ID during follow-up extending to September 2013. RESULTS: Thirteen ID (21% of 62) occurred; 10 (16% of 62) with high titre. Fifty-one patients (82%) were on primary prophylaxis (regular prophylaxis before the age of 2 and before the first joint bleed) from the median age of 11.4 months, 90% via a central venous access device. The initial product was rFVIII in 63% and pd-FVIII in 37%, moreover in 24% pd-FVIII was switched to rFVIII concentrate during the 75 EDs. Non-transient inhibitors developed in 9/51 (17.6%; 13.7% high titre) children with primary and in 4/11 (36.4%; 27.3% high titre) patients with secondary prophylaxis (P = 0.24). Overall, 74% had a high-risk genotype similarly distributed among the prophylaxis groups. The history of a major bleed enhanced ID (aHR, 4.0; 95% CI, 1.2-13.7), whereas FVIII treatment intensity or source and early implantation of ports did not increase ID risk. CONCLUSION: The cumulative incidence of ID was low notwithstanding prevalent high-risk mutations. Despite patient-related risk factors, our management involving early intensive primary prophylaxis via ports helps to prevent bleeds and lower the incidence of inhibitors.

Complications associated with central venous access device in children with haemophilia: a nationwide multicentre study in Finland.

Children with haemophilia require venous access for regular infusion of coagulation factors. A central venous access device (CVAD) ensures long-term access but associates with infectious and non-infectious complications with proposed risk factors of young age at initial CVAD implantation and presence of an inhibitor. Our aim was to evaluate the incidence and risk factors for complications associated with CVAD usage in a retrospective nationwide multicentre study in five Finnish Paediatric Haemophilia Treatment Centers. Our study investigated 106 CVADs in 58 patients with 137 971 CVAD days. The median access survival was 1159 CVAD days, and most often a malfunction led to CVAD removal after a long survival (median of 1640 CVAD days). We detected a very low bloodstream infection rate (0.12/1000 CVAD days). The presence of neutralizing inhibitor was a significant risk factor for infection. Heparin vs. saline flushing did not influence the CVAD outcome. We detected a lower infection rate than previously reported, although 90% of the patients were very young (<2 years) at first insertion (median age = 1.02 year). Port access was frequent after initial implantation: six patients (10%) used the port daily for immune tolerance induction therapy and 74% at least twice weekly for prophylaxis. Young age did not increase the risk of infections, as 59% of the CVAD-related infections were recorded in children over 6 years of age. Our national experience confirms the safety of prophylactic factor concentrate administration via ports even in very young children.

Systemic matrix metalloproteinase-8 and tissue inhibitor of metalloproteinases-1 levels in severe sepsis-associated coagulopathy.

BACKGROUND: Matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have recently been suggested to be involved in coagulation process. Our objectives were to observe systemic MMP-8 and TIMP-1 levels in patients with severe sepsis with or without disseminated intravascular coagulation (DIC) and to study their relationship with coagulation markers over time. METHODS: Our prospective pilot study included 22 patients with severe sepsis, nine (41%) of whom had overt DIC. We analysed MMP-8 and TIMP-1 serum concentrations by time-resolved immunofluorometric and enzyme-linked immunosorbent assays, respectively, on days 1, 2, 4 and 7 after the intensive care unit admission. Traditional coagulation tests were taken at the same time points. The results were compared between patients with and without DIC. Blood samples from 10 healthy volunteers were used to demonstrate normal levels. RESULTS: Both patient groups had elevated levels of MMP-8 and TIMP-1 as compared with healthy controls. TIMP-1 concentration was almost twofold in DIC patients compared with those without DIC on the first 2 days. MMP-8 was elevated only on day 2. TIMP-1 correlated positively with the severity of coagulation disturbance and with disease severity scores. MMP-8 correlated negatively only with platelet count. CONCLUSION: In this first human study, we could show that TIMP-1 is elevated in the early phase of sepsis-induced overt DIC, and it correlates both with degree of coagulopathy and disease severity. These findings suggest that TIMP-1 may play a role in the pathogenesis of DIC in septic patients.

Managing haemophilia for life: 4th Haemophilia Global Summit.

The 4th Haemophilia Global Summit was held in Potsdam, Germany, in September 2013 and brought together an international faculty of haemophilia experts and delegates from multidisciplinary backgrounds. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and explored global perspectives in haemophilia care, discussing practical approaches to the optimal management of haemophilia now and in the future. The topics outlined in this supplement were selected by the Scientific Steering Committee for their relevance and potential to influence haemophilia care globally. In this supplement from the meeting, Jan Astermark reviews current understanding of risk factors for the development of inhibitory antibodies and discusses whether this risk can be modulated and minimized. Factors key to the improvement of joint health in people with haemophilia are explored, with Carlo Martinoli and Víctor Jiménez-Yuste discussing the utility of ultrasound for the early detection of haemophilic arthropathy. Other aspects of care necessary for the prevention and management of joint disease in people with haemophilia are outlined by Thomas Hilberg and Sébastian Lobet, who highlight the therapeutic benefits of physiotherapy and sports therapy. Riitta Lassila and Carlo-Federico Perno describe current knowledge surrounding the risk of transmission of infectious agents via clotting factor concentrates. Finally, different types of extended half-life technology are evaluated by Mike Laffan, with a focus on the practicalities and challenges associated with these products.

Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations.

Severe von Willebrand's disease (VWD) type 3 is a rare autosomal-recessively inherited bleeding disorder, showing considerable genotypic heterogeneity. We investigated the phenotype in correlation with the genotype in Finnish type 3 VWD patients. Ten patients previously diagnosed with VWD type 3 treated at the Coagulation Disorder Unit in Helsinki University Hospital were re-evaluated for bleeding tendency and treatment. Phenotypic characterization included coagulation and platelet function testing confirming the diagnosis. The genotype was assessed by initial screening for the common c.2435delC mutation and subsequently if needed, by analysing all 51 coding exons of the von Willebrand factor gene. Our result confirmed the diagnosis of type 3 VWD for all 10 patients. We discovered two common mutations: nine of the 20 alleles (45%) were found to carry the c.2435delC frameshift mutation, previously described to be frequent in countries surrounding the Baltic Sea. The nonsense mutation c.4975C>T (p.R1659X) was found on 8/20 (40%) of the alleles. In addition, three novel mutations, a potential splice site mutation (c.874+2T>C) and two frameshift mutations (c.1668delC and c.2072delCCinsG) were found. Seven patients were homozygous and three compound heterozygous for the reported mutations. This study indicates that mainly two mutations (c.2435delC and p.R1659X) cause the majority of type 3 VWD in Finland. This result sets future standards for the genetic testing among the Finnish type 3 VWD population.

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.

Platelets significantly modify procoagulant activities in haemophilia A.

Haemophilia A replacement therapy is dosed according to patient's weight and plasma FVIII activity (FVIII:C). The FVIII interacts with platelet membrane but limited data on the impact of platelet procoagulant activity (PCA) are available in haemophilia A. Our aim was to characterize individual PCA in vitro in 20 adult haemophilia A patients at various FVIII:C levels. We detected thrombin generation in platelet-poor (PPP) and platelet-rich plasma (PRP) using: (i) calibrated automated thrombography (CAT) triggered with tissue factor, (ii) adhesion-induced PCA upon collagen and (iii) annexin V binding, expression of P-selectin and active glycoprotein (GP) IIbIIIa on platelets after stimulation of GPVI with collagen-related peptide. The FVIII:C levels varied between <1% and 37%. Thrombin generation was individual and strongly enforced by platelets and associated within the three methods. Range of thrombin generation was maximal (up to 30-fold) at FVIII:C levels 1-5%, underlining the impact of platelets in the presence of traces of replacement therapy. At FVIII:C > 5% platelet contribution in the variance faded. Platelet PCA and P-selectin exposure lead to a fivefold variation. Intriguingly, at FVIII:C < 1% thrombin generation in PPP associated negatively with platelet GPVI activation, suggestive of a regulatory interplay between plasma and platelets. In haemophilia A, the variability in thrombin generation is partially related to plasma FVIII:C, but mainly dependent on platelet procoagulant capacity. Annexin V binding and PCA in response to activation by collagen receptors contribute to this variability. In all, platelet PCA at least following collagen interaction significantly impacts thrombin generation in haemophilia A.

Levels of the cancer biomarker CA 19-9 are associated with thrombin generation in plasma from treatment-naïve pancreatic cancer patients.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with a hypercoagulable state and high mortality. Increases in the plasma levels of tumor marker carbohydrate antigen (CA) 19-9 are used in diagnosis and follow-up but have also been reported to precede venous thromboembolism (VTE). AIMS: We examined the association between CA 19-9 and thrombin generation (TG) in plasma from PDAC patients, as well as their association with coagulation biomarkers prior to pancreatic surgery. In addition, we determined the effect of commercial sources of CA 19-9 on TG. METHODS: We collected plasma from 58 treatment-naïve PDAC patients without any signs of VTE. We measured levels of CA 19-9, FVIII, fibrinogen, D-dimer, antithrombin and extracellular vesicle (EV) tissue factor (TF) activity and TG using a Calibrated Automated Thrombogram (CAT). The effect of different commercial sources of CA 19-9 on TG in Standard Human Plasma (SHP) was also studied. RESULTS: Patient plasma samples were divided into 4 preoperative groups based on the level of CA 19-9: none < 2, low = 3-200, high = 201-1000, and very high > 1000 U/mL. CA 19-9 levels were associated with several of the TG parameters, including endogenous thrombin potential, peak, and time to peak. CA 19-9 did not associate with any of the coagulation biomarkers. Spiking of SHP with CA 19-9 increased TG but this was decreased by an anti-TF antibody. CONCLUSIONS: CA 19-9 was associated with TG in patients prior to any pancreatic cancer treatments or signs of VTE. Some commercial sources of CA 19-9 enhanced TG in SHP seemingly due to contaminating TF.

Current challenges of pharmacovigilance in bleeding disorders: converting the burden to benefit.

SUMMARY: Safety surveillance studies have proven essential in research and development of new biological therapies for bleeding disorders as well as other diseases. Although product safety regarding HIV, hepatitis, and other blood-borne infections is currently excellent, potential new infectious agents require continued vigilant monitoring. Inhibitor development is the most common serious side effect of haemophilia replacement therapy. Several aetiological factors associated with inhibitors have been identified, but their true impact is still largely unknown. Moreover, whether plasma-derived and recombinant factor products differ in their immunogenic profiles is an unresolved issue. Coagulation factor products under development and those currently on the market require uniform, long-term surveillance. The European Haemophilia Safety Surveillance (EUHASS) project was recently established to meet these goals. The pharmaceutical industry and clinicians face common challenges complying with these requirements. In rare diseases like haemophilia, obtaining adequate patient numbers poses a challenge. Another challenge is a lack of methods for assessing disease severity, a surprising deficiency in the era of modern medical and laboratory technology. National and international registries can be used to gather required safety surveillance information. Simultaneously, clinicians benefit from well-organized registry data in their daily practice and harmonize the quality of comprehensive haemophilia care by homogeneous follow-up platforms. Experience with such registries comes, for example, from Europe (PEDNET), the USA (CDC/UDC), the UK (UKHCDO), and Sweden (Malmö). It is important to commit to future pharmacovigilance efforts, aiming at high-quality safety surveillance programmes at both the pharmaceutical research community and clinical levels.

FEIBA prophylaxis in haemophilia patients: a clinical update and treatment recommendations.

In patients with severe haemophilia and inhibitors, regular factor VIII inhibitor bypassing activity (FEIBA) prophylaxis has been shown to reduce the frequency of bleeding by up to 85% and to improve patient quality of life. FEIBA is well tolerated; the incidence of thrombotic events and of allergic reactions is extremely low. The concept of prophylaxis in haemophilia patients with inhibitors is relatively new and some clinicians may be unsure of how to use FEIBA in this context. These treatment recommendations, based on published evidence plus the collective experience of a group of haematologists (with practical knowledge of managing inhibitor patients with FEIBA prophylaxis), are intended to provide guidance to clinicians considering initiating and maintaining patients on FEIBA prophylaxis with specific focus on practical aspects of patient selection, dosing, monitoring and stop criteria.

Management of post-partum haemorrhage.

Management of post-partum haemorrhage (PPH) involves the treatment of uterine atony, evacuation of retained placenta or placental fragments, surgery due to uterine or birth canal trauma, balloon tamponade, effective volume replacement and transfusion therapy, and occasionally, selective arterial embolization. This article aims at introducing pregnancy- and haemorrhage-induced changes in coagulation and fibrinolysis and their relevant compensatory mechanisms, volume replacement therapy, optimal transfusion of blood products, and coagulation factor concentrates, and briefly cell salvage, management of uterine atony, surgical interventions, and selective arterial embolization. Special attention, respective management, and follow-up are required in women with bleeding disorders, such as von Willebrand disease, carriers of haemophilia A or B, and rare coagulation factor deficiencies. We also provide a proposal for practical instructions in the treatment of PPH.

Migration at early age from a high to a lower coronary heart disease risk country lowers the risk of subclinical atherosclerosis in middle-aged men.

BACKGROUND: Study of migrants offers a natural model to assess environmental risk of coronary heart disease (CHD) in countries differing in CHD occurrence. In Sweden, CHD risk has been markedly lower than in Finland from where a large migration occurred in the 1970s. OBJECTIVES: To study the structural and functional markers of subclinical atherosclerosis in twin pairs discordant for migration with the main focus on age at migration, length of residence and integration into Swedish society after migration from a high to a lower CHD risk country. METHODS: Carotid intima-media thickness (IMT) and brachial artery endothelial function (EF) were assessed with high-resolution ultrasound and a set of cardiovascular, socio-economic and psychosocial risk factors were estimated in 76 middle-aged male twin pairs discordant for migration from Finland to Sweden. RESULTS: Men who had migrated in adolescence had lower IMT values compared with their co-twins living in Finland (0.665 +/- 0.114 vs. 0.802 +/- 0.167 mm, P = 0.009). Also men who integrated well to Swedish society had lower (0.720 +/- 0.154 vs. 0.799 +/- 0.207 mm, P = 0.013) IMT values than their twin brothers living in Finland. Associations between IMT and migration age and between IMT and integration remained significant in multivariate analyses of several CHD risk factors. The intrapair difference in IMT was significantly associated with immigration age and integration (ANOVA, P = 0.0082), the difference being greatest among pairs where the brother living in Sweden had migrated at early age and integrated well to Swedish society. EF was better in men who had migrated to Sweden before the age of 21 years, but not later, compared with their co-twins in Finland (6.4 +/- 4.6% vs. 3.8 +/- 3.6%, P = 0.025). CONCLUSIONS: Migration at an early age and good integration are beneficial to vascular health associated with moving from a high to a lower CHD risk country, suggesting that an environment-sensitive period influences atherogenesis before adulthood.

Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.

A 12-month-old boy and his 16-year-old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liver-kidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre- and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow-up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liver-kidney transplantation combined with pre- and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation.

European principles of haemophilia care.

As the management of haemophilia is complex, it is essential that those with the disorder should have ready access to a range of services provided by a multidisciplinary team of specialists. This document sets out the principles of comprehensive haemophilia care in Europe. Within each country there should be a national organization which oversees the provision of specialist Comprehensive Care Centres that provide the entire spectrum of clinical and laboratory services. Depending upon the size and geographical distribution of the population, a network of smaller haemophilia centres may also be necessary. There should be arrangements for the supply of safe clotting factor concentrates which can also be used in home treatment and prophylaxis programmes. A national register of patients is recommended along with collection of treatment statistics. As comprehensive haemophilia care is multidisciplinary by nature, the need for education and research programmes for all staff members is emphasized: Members of the Interdisciplinary Working Group not represented in the list of authors are mentioned in Section 4 of this document.