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Background: A successful outcome of pregnancy requires an efficient uteroplacental vascular system. Since this system may be compromised by disorders of haemostasis associated with a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S., Methods: We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia 571 had 1524 pregnancies; of 541 control women 395 had 1019 pregnancies. The controls were partners of male members of the EPCOT cohort or acquaintances of cases. We analysed the frequencies of miscarriage (fetal loss at or before 28 weeks of gestation) and stillbirth (fetal loss after 28 weeks of gestation) jointly and separately., Findings: The risk of fetal loss was increased in women with thrombophilia (168/571 vs 93/395; odds ratio 1.35 [95% Cl 1.01-1.82]). The odds ratio was higher for stillbirth than for miscarriage (3.6 [1.4-9.4] vs 1.27 [0.94-1.71]). The highest odds ratio for stillbirth was in women with combined defects (14.3 [2.4-86.0]) compared with 5.2 (1.5-18.1) in antithrombin deficiency, 2.3 (0.6-8.3) in protein-C deficiency, 3.3 (1.0-11.3) in protein-S deficiency, and 2.0 (0.5-7.7) with factor V Leiden. The corresponding odds ratios for miscarriage in these subgroups were 0.8 (0.2-3.6), 1.7 (1.0-2.8), 1.4 (0.9-2.2), 1.2 (0.7-1.9), and 0.9 (0.5-1.5). Significantly more pregnancy terminations had been done in women with thrombophilia than in controls (odds ratio 2.9 [1.8-4.8]); this discrepancy was apparent in nine of 11 participating centres and for all thrombophilia subgroups., Interpretation: Women with familial thrombophilia, especially those with combined defects or antithrombin deficiency, have an increased risk of fetal loss, particularly stillbirth. Our findings have important implications for therapy and provide a rationale for clinical trials of thromboprophylaxis for affected women with recurrent fetal loss.

Introduction: Patients suffering from von Willebrand disease (VWD) have a variety of bleeding symptoms and require both outpatient care for treatment and, in more severe cases, hospitalization. Aim: To investigate the impact of having VWD on frequency of hospitalization compared to a control group and to evaluate whether regular replacement therapy (prophylaxis) is associated with reduction in the number of hospitalizations. Methods: Linkage of national population‐based registries was used in the Congenital Bleeding Disorders study in Sweden (CBDS). Data were from the von Willebrand Disease Prophylaxis Network (VWD PN). Results: The national registries contained 2790 subjects with a diagnosis of VWD between 1987 and 2009. A total of 13 920 age‐ and gender‐matched controls were identified. There were 2.0 times (range 1.5‐2.5) as many inpatient hospitalizations among subjects with VWD compared to controls. The most common causes of hospitalization were gastrointestinal (GI) bleeding (n = 232 as primary diagnosis), menorrhagia (n = 198) and epistaxis (n = 192). Outpatient visits per year were also twice as common among those with VWD. From the VWD PN, 105 subjects were included (VWD type 3, 52.4%; type2A, 22.9%; type 1, 12.4% and other types, 3.9%). A total of 122 hospitalizations due to bleeding episodes, dominated by GI bleeds, were analysed. Significantly fewer hospitalizations occurred after initiation of prophylaxis (75 prior to and 45 after, P = .006). Conclusion: Our study indicates that subjects with VWD have a considerably higher consumption of healthcare resources compared to controls and that initiation of prophylaxis may reduce the number of hospitalizations due to bleeding. [ABSTRACT FROM AUTHOR]

Introduction People with severe haemophilia A have reportedly impaired health related quality of life (utility) mainly due to recurrent bleeding, arthropathy and treatment burden. Aim To estimate utilities and evaluate their potential correlates - most importantly the joint status - among people with severe haemophilia A. Methods In this cross-sectional study, eligible participants had severe haemophilia A, were aged ≥15, negative for factor VIII inhibitor and included in the KAPPA register of Denmark, Norway and Sweden. Data on demographics, treatment history, haemophilia joint health score, and EQ-5D utility were obtained from the register. We used box plots to present utilities and joint status and ordinary least squares regression to evaluate correlates of utilities. Participants were consecutively enrolled in the KAPPA register between April 2013 and June 2016. Results Overall, 173 participants with median age of 34 (interquartile range: 25-45) were included. Twelve (6.9%) participants were on episodic treatment while 161 (93.1%) were treated using prophylaxis. Concomitant diseases and positive inhibitor history were reported for 73 (43.2%) and 21 (12.1%) participants, respectively. The highest median utility (1.0) was observed among those aged <29 on prophylaxis and those aged 30-44 who had started prophylaxis by age 3. In the multi-variable regression, joint scores of 16-25 (Coef. −0.18, 95% CI: −0.30, −0.06), 26-35 (Coef. −0.21, 95% CI: −0.36, −0.06) and >35 (Coef. −0.37, 95% CI: −0.52, −0.23) were associated with lower utilities. Conclusion Moderate to severe joint manifestations are associated with reduced utilities among persons with severe haemophilia A. [ABSTRACT FROM AUTHOR]

Introduction Looking into the future is difficult and sometimes hazardous. A reliable look into haemophilia treatment in 2030 should be based on history and contemporary progress as well as dilemmas. Today, the issue of inhibitors overshadows the entire haemophilia community together with lack of treatment for large parts of the world's persons with haemophilia. Aims The aim of this paper was to provide a perspective on haemophilia treatment in 2030 and its provenance. Methods Literature review on history, treatment of haemophilia today as well as of emerging therapies give a base for the author's opinion on haemophilia treatment in 2030. Results Development of haemophilia treatment has virtually exploded during the last decade and a number of new clotting factor concentrates and alternative approaches are in the pipeline. Conclusion The collection of treatment resources that we can see on the horizon gives hope that each person with haemophilia will get the care needed in 2030. The products used will be directed by individual needs and tailored to regional and local situations. [ABSTRACT FROM AUTHOR]

Introduction We previously showed that pharmacokinetic-guided prophylaxis ( PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII ( FVIII) levels and area under the curve ( AUC) with breakthrough bleeding have not been investigated. Aim The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. Methods Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. Results During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL−1, with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding ( P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL−1 was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. Conclusion When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL−1 provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens. [ABSTRACT FROM AUTHOR]

Introduction Aim: To use Pharmacokinetic ( PK) simulations to illustrate potential differences in clinical outcomes between prophylaxis with conventional recombinant factor VIII (r FVIII) and rFVIIIFc, an extended half-life rFVIII covalently fused to the Fc domain of human IgG1. Methods: Population PK estimates from 180 ( rFVIIIFc) and 46 ( rFVIII) severe haemophilia A patients were used to simulate FVIII activity over time at various rFVIIIFc dosing regimens compared to rFVIII 30 IU kg−1 three times weekly in a typical adult patient. Results: rFVIII dosed 3x30 IU kg−1 weekly gave trough levels of 2.7, 2.8 and 0.7 IU dL−1, and time spent below 1, 3 and 5 IU dL−1 of 0.2/1.2/2.3 days week−1. rFVIIIFc 2 x 45 IU kg−1 gave higher troughs (4.4 and 1.7 IU dL−1) and shorter time spent below 1, 3 and 5 IU dL−1 (0/0.6/1.3 days week−1), with same total factor consumption. rFVIIIFc 2 x 30 IU kg−1 gave similar troughs (3.0 and 1.2 IU kg−1) and time spent below 1, 3 and 5 IU dL−1 (0/1.0/2.1 days week−1), despite total factor consumption being reduced by one-third. The same dose and interval of rFVIIIFc (3 x 30 IU kg−1) gave substantially higher troughs (7.8, 8.5 and 3.3 IU dL−1) and markedly shorter time spent below 1, 3 and 5 IU dL−1 (0/0/0.4 days week−1). Conclusion: The lower clearance of rFVIIIFc compared to conventional rFVIII gives rFVIIIFc the potential of improved bleed prevention and reduced injection frequency at similar factor consumption. Although additional clinical data are required to confirm the conclusions, the simulations clearly show the potential of rFVIIIFc of increased flexibility to tailor treatment to the individual patient, and to advance the standard of care in haemophilia. [ABSTRACT FROM AUTHOR]

Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life ( HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate ( aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ≥14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ≥50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score ( P = 0.021), role - physical ( P = 0.042), bodily pain ( P = 0.015), and social functioning ( P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment ( P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment. [ABSTRACT FROM AUTHOR]

. Nonacog alfa, a recombinant factor IX (FIX) used for the treatment of haemophilia B, was approved in Europe in 1998. In accordance with European Medicines Agency requirements, a registry study was conducted from 2002 to 2009. A reformulated iso-osmotic version was approved for European use in 2007. This study was conducted to evaluate the safety of nonacog alfa in a usual care setting, and provide clinical trial and postmarketing surveillance data support. This open-label, non-interventional, prospective observational cohort study (registry) comprised 52 sites in nine European countries. Patients with haemophilia B receiving nonacog alfa in either formulation for prevention or treatment were followed on a usual care schedule. A total of 218 patients were enrolled, of whom 66 (30.3%) were <18 years of age. Haemophilia severity was evenly distributed, with baseline FIX activity of <1%, 1-5% and >5% in 33.3%, 36.6% and 30.1% of patients, respectively. One hundred thirty-eight patients received the original formulation alone; 80 switched to or received only the new formulation. There was a low incidence of events of special interest (ESIs), with less-than-expected therapeutic effect in five patients (2.2%), inhibitor development in two (0.9%), thrombosis in one (0.5%) and allergic events in eight (3.7%). These accounted for the majority of the 15 serious AEs reported in six patients. Six patients discontinued because of AEs, primarily related to hypersensitivity. Nonacog alfa was shown to be safe for the treatment of haemophilia B, with a low incidence of serious AEs and ESIs. [ABSTRACT FROM AUTHOR]

. Increased or maintained health and quality of life (HRQoL) are essential goals in health care among patients with a chronic disease. To gain an understanding of HRQoL in patients with haemophilia at the Haemophilia Treatment Centre in Malmö, Sweden, patients seen from 2004-2008 were asked to complete the Short form Health Survey, SF-36, also answering to what extent haemophilia, physically and mentally, interferes with their daily life at their annual check-up. Data were extracted from the UMAS Haemophilia Database. Interference of haemophilia in daily life was estimated using a Visual Analogue Scale. A total of 105/144 haemophilia patients were included in the study (73%); 28 mildly, 21 moderately and 56 severely affected. The median age of patients at study entry was 44.0 years (range 18-84 years). The comparison of SF-36 data of Swedish haemophilia patients with the general Swedish male population yielded no significant differences in age groups 15-24, 25-34 and 65-74 years. Patients in age groups 35-44 years, 45-54 years and 55-64 years were significantly impaired in some of their HRQoL domains. For severely affected patients who filled in SF-36 over a period of 5 years no statistical differences in HRQoL were found. For patients undergoing orthopaedic surgery HRQoL increased in most SF-36 domains. Patients reported in general on the VAS that they feel 'somehow' interfered in their daily life due to haemophilia. The results indicate a need for continuous monitoring of HRQoL to identify an increased need of care in the ageing haemophilia population. [ABSTRACT FROM AUTHOR]

. Haemophilia, if not properly managed, can lead to chronic disease and lifelong disabilities. The challenges and issues in infants/young children are different from those in older children and adults although episodes of bleeding still predominate as the diagnostic trigger. Awareness of clinical manifestations and treatment complications are crucial in instituting appropriate management and implementing preventive strategies. Currently, inhibitor development is a challenging complication of paediatric haemophilia and prophylaxis is emerging as the optimal preventive care strategy. In this section we will review some important aspects of haemophilia in children including early prophylaxis, current evidence relating to inhibitor development, including the aims of the SIPPET study which is already ongoing and involves boys <6 years, and the potential of immune tolerance therapy for eradicating the inhibitor and permitting a resumption of standard dosing schedules. [ABSTRACT FROM AUTHOR]

Summary. In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandva˚rds-och lākemedelsförma˚nsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvārdering) was called upon to evaluate treatment of haemophilia A and B and von Willebrand's disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important. [ABSTRACT FROM AUTHOR]

Severe haemophilia and reduced bone density can negatively influence perception of patient's health-related quality of life (HRQoL), especially considering future aspects, the risk of losing independence or pain suffering. The aim of this study was to assess levels of HRQoL in severe haemophilia patients and to compare HRQoL to those of the general population as well as to determine whether reduced bone density is correlated to the perceived HRQoL. Patients were divided into two groups based on timing of being treated with prophylaxis: Group A (started prophylaxis at age of ≤3 years; n = 22); Group B (at age of >3 years; n = 15). The bone mineral density (BMD g cm) of different measured sites was measured by dual energy X-ray absorptiometry (DXA). HRQoL was assessed using SF-36 questionnaire. Group A have mean BMD T-score >−1.0 (i.e. normal score) at all measured sites, and have almost similar scores in the SF-36 domains compared with the reference population. Group B have mean BMD T-score <−1.0 at hip region, and >−1.0 at lumbar spine and total body, and their scores in the SF-36 domains were lower compared with the reference population. Moreover, significant correlations were found between BMD at femoral neck and total body with physical domains. With adequate long-term prophylaxis since early childhood, adult patients with haemophilia report a comparable BMD and HRQoL to the Swedish reference population. Reduced BMD in group B correlated with impaired physical health, which underscores the importance of early onset of adequate prophylactic treatment. [ABSTRACT FROM AUTHOR]

Assessing response to treatment with bypassing agents presents a substantial challenge in the treatment of patients with haemophilia and inhibitors. Rapid and accurate identification of bleeding episodes that are non-responsive to bypassing therapy with either Factor Eight Inhibitor Bypassing Activity (FEIBA; Baxter AG) or recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S) is essential to guide treatment decisions and optimize patient outcomes through early intervention. Although both bypassing agents are effective, differential responses to therapy necessitate multiple therapeutic options. This article provides a consensus definition for non-life-threatening joint and muscle bleeds that are non-responsive to bypassing agents. An international panel of seven physicians met in December 2008 to develop the consensus definition using a modified National Institutes of Health Consensus Development Conference method. The consequent definition of non-life-threatening bleeding episodes that are non-responsive to bypassing treatment provides a global picture of the condition of the patient during such an event. Identification of non-responsiveness is based on various criteria: pain, swelling/tension, mobility, patient perception and laboratory parameters. Criteria can be assessed subjectively by the patient/parent and/or objectively by the clinician. Although the precise timing of each determination should be at the discretion of the physician, bleeds should be considered non-responsive if the clinical situation meets the specified criteria 24 h from the start of treatment. Although it is not intended to replace clinical judgment, this definition can guide the optimal course of treatment for patients with haemophilia and inhibitors. [ABSTRACT FROM AUTHOR]

The article present a study which compares the phenotype and genotype in patients with haemophilia. Methods used to evaluate the bleeding tendency and carrier status are offered. Results indicate weak correlation between bleeding score (BS) and clotting factor activity and an increased bleeding tendency even at clotting factor

In patients with severe haemophilia, spontaneous bleeding into joints initiates a sequence of events culminating in disabling arthropathy. Early evidence from Sweden suggested that clotting factor prophylaxis improved patient outcomes. Recent randomized, controlled trials comparing prophylaxis with on-demand treatment have definitively shown that prophylaxis reduces bleeding and improves joint outcomes in patients with severe haemophilia A. Available evidence also supports the effectiveness of prophylaxis in patients with haemophilia B. In the United States, fewer than half of all patients with severe haemophilia A or B are treated with prophylaxis, and in those receiving such treatment, adherence to prophylactic treatment regimens is low in many age groups. Barriers to prophylaxis include cost, difficulties associated with venous access and the time required for prophylactic infusions. Although concerns around adherence play an important role in the willingness of physicians to prescribe prophylaxis, individualized prophylactic regimens may help increase patient adherence. Clotting factors that are more convenient and less time-consuming to infuse also may improve adherence to prophylactic therapy. By promoting rigorous adherence to prophylactic clotting factor therapies, physicians may be able to help preserve joint function in patients with severe haemophilia. [ABSTRACT FROM AUTHOR]

The bypassing agents factor eight inhibitor bypassing activity (FEIBA) anti-inhibitor coagulant complex and recombinant activated factor VII (rFVIIa) have been established as safe and effective therapies for treating bleeding episodes in haemophilia patients with inhibitors. However, the efficacy of each bypassing agent can vary, and neither agent is universally effective. The reasons for such variability have yet to be confirmed, but may involve patient-specific factors and the mechanisms of action (MOAs) and pharmacokinetic profiles of these two agents. This issue underscores the necessity of both products in the comprehensive care of patients with haemophilia and inhibitors. The objective of this review is to discuss the evidence of a differential haemostatic response to bypassing agents and the potential roles of MOA and patient-specific factors in contributing to the differences in response. [ABSTRACT FROM AUTHOR]

Severity assessment of patients with haemophilia A (HA) is traditionally based on FVIII activity (FVIII:C). Clinical phenotype of HA patients often differs between individuals with the same FVIII:C determined with clotting and chromogenic assays. The aim of this study was to assess the influence of the FVIII:C on thrombin generation (TG) assay parameters both in vitro and ex-vivo postinfusion plasma. For in-vitro approach, influence of FVIII:C was evaluated on TG parameters in several dilutions of a normal plasma pool with commercial FVIII-depleted-plasma (FVIIIDP) and in others experiments, adding increasing amounts of different commercial FVIII concentrates (Fanhdi, Haemate-P, Hemofil-M and Kogenate Bayer) to FVIIIDP. In a series of 50 postinfusion samples, from HA patients of different severity, we assayed TG and FVIII:C (chromogenic and clotting). In vitro experiments, the 50% of maximum TG peak (TGMP) was achieved using only 5% FVIII:C and the TGMP was obtained with 40% of normal VIII:C. Impaired response compared with normal plasma was found in FVIIIDP using addition of increasing amounts of different commercial FVIII concentrates. An overall good correlation between the two FVIII assays was observed ( y = 0.9115x − 0.273, r = 0.975, P < 0.001); TGMP and the Lag-Phase-Time (LPT) provided some discrepant results when compared with the total range of FVIII:C measurements. In contrast, correlations for TGMP, LPT and endogenous thrombin potential were improved in samples restricted to FVIII:C <5%. We conclude that TG parameters tentatively could be a tool to tailor the global haemostatic capacity in haemophilic patients. [ABSTRACT FROM AUTHOR]

It has been previously shown that patients with severe haemophilia and not receiving any prophylactic treatment render a high risk of reduced bone mineral density. The purpose of this study was to evaluate bone mineral density (BMD) in patients with haemophilia of different severity types and treatment. The study group consisted of 26 patients with severe haemophilia (aged 33.6 ± 2.1) and 16 patients with mild haemophilia (aged 40.2 ± 3.3). The BMD (g cm−2) was measured by dual-energy X-ray absorptiometry (DXA). Physical activity was assessed by a self-report questionnaire. Physical activity was scored as duration (h week−) and as metabolic physical activity score by weighing the intensity (MET-h week−1). Joints were evaluated according to a physical examination score. There was no significant difference in BMD at lumbar spine L1–L4 (mild, 1.214 vs. severe, 1.175; P = 0.329), total hip (1.085 vs. 1.001, P = 0.114), femoral neck (1.036 vs. 0.977, P = 0.265), trochanter (0.896 vs. 0.820, P = 0.131) and whole body (1.215 vs. 1.183, P = 0.325) between those with mild and severe haemophilia. Based on Z-score, both groups had normal BMD (Z score >−1). In patients with severe haemophilia, there was a significant correlation between joint evaluation score and BMD at total hip ( P < 0.0001), femoral neck ( P = 0.0003) and trochanter ( P = 0.003). Physical activity did not correlate to disease severity. We did not observe a correlation between BMD and severity of haemophilia. The results indicate that the use of factor prophylaxis since early childhood may preserve normal BMD in severe haemophilia. [ABSTRACT FROM AUTHOR]

Although von Willebrand disease (VWD) is now well-described, many facets of diagnosis and management continue to be debated. The diagnosis of type 1 disease can be difficult but recent genetic analyses help to distinguish many factors which can influence von Willebrand factor (VWF) levels and bleeding phenotype. Type 2 disease (functional abnormalities) includes a particularly interesting group of disorders with faulty binding between VWF and FVIIIC (Normandy) where treatment methods need careful consideration. Type 3 VWD is the most severe form of VWD and a new international study is underway to examine the use of prophylaxis. [ABSTRACT FROM AUTHOR]

We and others have previously shown that inhibitor containing plasma from patients with congenital haemophilia A sometimes reacts less with von Willebrand factor (VWF) containing concentrates compared with highly purified plasma-derived or recombinant factor VIII (FVIII) concentrates. To further substantiate the haemostatic role of a variation in inhibitor reactivity with different FVIII concentrates, we compared the inhibitor titres from 11 plasma samples against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested: Fandhi (Grifols) which contains VWF with a final ratio of approximately 1 (VWF IU per IU FVIII:C); Haemate (CSL Behring) with a ratio of 2.5 and Haemofil M (Baxter), a monoclonal antibody-purified concentrate containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer (Bayer) containing no VWF was included in the panel. A statistically significant difference in measured titres against the four concentrates was found. The inhibitor titre needed to inhibit 50% maximum thrombin generation was lowest for Kogenate Bayer and highest and similar for Fandhi and Haemate. This study confirms the results from previous research regarding variation of inhibitor reactivity against different concentrates and further shows that the VWF containing concentrates Fandhi and Haemate added to FVIII-deficient plasma with the presence of inhibitor generate more thrombin than do the purified concentrates Haemofil M and Kogenate Bayer. A further interesting aspect could be that bypass therapy may have an increased efficacy when infused together with FVIII concentrates containing VWF. However, the clinical implications of all these findings in vitro need to be established. [ABSTRACT FROM AUTHOR]

Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enrol cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI. [ABSTRACT FROM AUTHOR]

We report the case of a patient with mild haemophilia A, due to a Tyr2105Cys mutation in exon 22 of the C1 domain, who developed a high-titre factor VIII inhibitor (maximum titre 1600 BU) with recurrent severe haemorrhages and fatal intracranial bleeding. Based on published data, it appears that although this mutation occurs rarely in patients with mild or moderate haemophilia A, it is frequently associated with the development of high-titre inhibitors. [ABSTRACT FROM AUTHOR]

The primary aim of this study was to investigate the possible relationship between coagulation factor level and bleeding frequency during prophylactic treatment of haemophilia after stratification of the patients according to joint scores. The secondary aim was to obtain a systematic overview of the doses of coagulation factors prescribed for prophylaxis at the Malmo haemophilia treatment centre during a 6-year period. A retrospective survey of medical records for the years 1997-2002 and pharmacokinetic study results from the 1990s was complemented by collection of blood samples for coagulation factor assay when needed. Information on the dosing and plasma levels of factor VIII or factor IX, joint scores and incidence of bleedings (joint bleeds and `other bleeds') was compiled. The patients were stratified by age (0-6, 7-12, 13-18, 19-36 and >36 years) and joint score (0, 1-6 and >6). Individual pharmacokinetic parameters of plasma coagulation factor activities (FVIII:C and FIX:C) were estimated. Trough levels during the treatment were calculated, as well as the number of hours per week of treatment during which plasma FVIII:C/ FIX:C fell below a 1, 2 or 3% target level. Fifty-one patients with haemophilia A (two moderate, 49 severe) and 13 with haemophilia B (all severe) were included, yielding data for 364 patient-years of treatment. There was a wide range of dosing schedules, the most common ones being three times a week or every other day for FVIII and twice a week or every third day for FIX. The overall relationship between FVIII:C/FIX:C levels and incidence of joint bleeding was very weak, even after stratification of the patients according to joint score. There was no relationship between coagulation factor level and incidence of other bleeds. In this cohort of patients on high-dose prophylactic treatment, dosing was based more on clinical outcome in terms of bleeding frequency than on the aim to maintain a I % target level of FVIII:C/ FIX:C. Some patients did not bleed in spite of a trough level of <1% and others did in spite of trough levels >3 %. The practical implication of our findings is that dosing in prophylactic treatment of haemophilia should be individualized. Thus, proposed standard regimens should be implemented only after careful clinical consideration, with a high readiness for re-assessment and individual dose tailoring. [ABSTRACT FROM AUTHOR]

Summary. Clotting factor preparations are expensive and not readily available in all parts of the world. We are still facing shortages due to limited production. Thus, it is obvious that clotting factor therapy should be optimised as far as possible. The judicious use of pharmacokinetic principles should be one of the fundaments of dosing. There are several pitfalls in studies of clotting factor pharmacokinetics, such as discrepancies between assays, inadequate blood sampling protocols, problems to define the administered dose, uncertainty in the estimation of plasma volume for in vivo recovery calculation, and post-infusion activation of the clotting factor. Thus, while the pharmacokinetics of factor VIII is well characterised there are some discrepancies in the literature on factor IX. Recombinant factor VIIa is useful to treat haemorrhages in haemophilia complicated by inhibitors. The pharmacokinetics of VIIa has been investigated, however, the relationship between plasma level of VIIa and effect needs further exploration. Important applications of clotting factor pharmacokinetics include optimising the treatment and improving its cost-effectiveness during long-term prophylaxis as well as during bleeding episodes and surgery. [ABSTRACT FROM AUTHOR]

Background: Global haemostatic tests are often abnormal in critically ill patients, secondary to activation or consumption of coagulation factors or inhibitors. Methods for analysing plasma levels of these factors are, however, not widely available, and the predictive value of global tests is not known. We examined the clinical applicability to predict the outcome of the global haemostatic tests used at most hospitals.Methods: Blood was collected from patients within 6 h of admission to an intensive care unit (ICU) and tested regarding platelet count, International Normalized Ratio (INR), and activated partial thromboplastin time (APTT). Ninety-two patients with platelet counts <100 x 10(9) l(-1), INR > 1.36 and/or APTT >45 s were included in a study group, and an additional 92 patients with a comparable age and sex distribution, but not fulfilling these laboratory criteria, constituted a control group. The following data were recorded for each patient: number of days in the ICU and hospital; alive or deceased when released from the ICU and hospital; survival at 30 days and 180 days.Results: Survival upon discharge from the ICU and hospital was significantly reduced in the study group. This was especially pronounced in patients with medical disorders, whereas the survival rate was slightly higher in surgery patients. Expressing the survival predicting ability of the screening tests as odds ratios for all patients (study and control groups together) indicated that prolonged APTT in particular foretold a lower survival rate at studied time-points after admission to the ICU.Conclusions: The global haemostatic tests INR and APTT can predict survival in critically ill patients, and prolonged APTT in particular seems to be associated with a negative prognosis. [ABSTRACT FROM AUTHOR]

Haemophilia is a recessively inherited coagulation disorder, in which an X-chromosome mutation causes a deficiency of either coagulation factor VIII (FVIII) in haemophilia A, or factor IX (FIX) in haemophilia B. Intravenous administration of FVIII or FIX can be used to control a bleeding episode, to provide haemostasis during surgery or for long term prophylaxis of bleeding. In special cases, activated factor VII (FVIIa) may be used instead of FVIII or FIX. The aim of this work is to review the pharmacokinetics of FVIII, FIX and FVIIa and to give an outline of the use of pharmacokinetics to optimise the treatment of patients with haemophilia. The pharmacokinetics of FVIII are well characterised. The systemic clearance (CL) of FVIII is largely determined by the plasma level of von Willebrand factor (vWF), which protects FVIII from degradation. Typical average CL in patients with normal vWF levels is 3 ml/h/kg, with an apparent volume of distribution at steady state (Vss) that slightly exceeds the plasma volume of the patient, and the average elimination half-life (t1/2) is around 14 hours. There are still some discrepancies in the literature on the pharmacokinetics of FIX. The average CL of plasma-derived FIX seems to be 4 ml/h/kg, the Vss is 3 to 4 times the plasma volume and the elimination t1/2 often exceeds 30 hours. FVIIa has a much higher CL (average of 33 ml/h/kg), and a short terminal t1/2 (at 2 to 3 hours). The Vss is 2 to 3 times the plasma volume. Since the therapeutic levels of coagulation factors are well defined in most clinical situations, applied pharmacokinetics is an excellent tool to optimise therapy. Individual tailoring of administration in prophylaxis has been shown to considerably increase the cost effectiveness of the treatment. Dosage regimens for the treatment of bleeding episodes or for haemostasis during surgery are also designed using pharmacokinetic data, and the advantages of using a constant infusion instead of repeated bolus doses have been explored. The influence of antibodies (inhibitors) on the pharmacokinetics of FVIII and FIX is in part understood, and the doses of coagulation factor needed to treat a patient can tentatively be calculated from the antibody titre. In conclusion, therapeutic monitoring of coagulation factor levels and the use of clinical pharmacokinetics to aid therapy are well established in the treatment of patients with haemophilia. [ABSTRACT FROM AUTHOR]

The concept of using pharmacokinetics for prophylactic dose tailoring with limited blood sampling in clinical practice has been demonstrated for factor VIII but not for factor IX. The pharmacokinetics of factor IX are more complicated than for factor VIII and also differ between plasma-derived and recombinant factor IX. Therefore, the pharmacokinetics of factor IX need to be further explored in clinical trials including comparative studies of prophylaxis with different factor IX concentrates. These are the main conclusions drawn from two of the last manuscripts written by Professor Sven Björkman and published in Haemophilia. Professor Björkman suddenly and unexpectedly died last summer. Thanks to the academic network created around his skill and through his enthusiasm for the pharmacokinetics of clotting factors and ability to convey his wisdom to others, this work will continue. Sven Björkman opened a new era in hemophilia prophylaxis. [ABSTRACT FROM AUTHOR]