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Objective: To explore key factors for successful support in women with moderate or severe Von Willebrand disease (VWD) who are faced with heavy menstrual bleeding (HMB) and surgery., Design: A qualitative study design with focus-group interviews and thematic analysis of the discussions., Settings and Population: Eleven VWD women aged 41-68 years (median age 58 years) who had had a hysterectomy or bipolar radiofrequency ablation (BRA) because of HMB participated in this study. Three of the 11 participants had VWD diagnosed before surgery. Two focus groups were conducted in the summer of 2012. Patients were identified through participation in a nationwide study on Von Willebrand disease in the Netherlands (WiN study). Inclusion criteria were at least 18 years of age, fluent in Dutch, diagnosed with VWD (based on Von Willebrand factor (VWF) antigen and/or activity levels < 30 IU/dL) and previous surgical therapy for HMB., Findings: The following key factors were identified during focus-group interviews: receiving information, proactive support from providers and considering bleeding disorders as a cause of HMB. Other topics were as follows: experiences with VWD and/or surgery, how relieved patients were when menses stopped, patients hoped that in future, providers would work better together so that women receive the best care., Conclusions: In this focus-group study among women with VWD who underwent surgery because of HMB, support by professionals could be improved by considering a bleeding disorder in women with HMB, providing information about different types of surgery and shared decision-making regarding type of interventions., (© 2018 John Wiley & Sons Ltd.)

Introduction: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy., Aim: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed., Methods: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL -1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines., Results: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL -1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL -1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%)., Conclusion: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: Patients with Von Willebrand disease (VWD) are regularly treated with VWF-containing concentrates in case of acute bleeding, trauma and dental or surgical procedures., Aim: In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate ® P) in patients with VWD was evaluated., Patients/methods: Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate ® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII-based treatment regimens were compared to predefined target levels in national guidelines., Results: In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20 IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act., Conclusion: High VWF:Act and accumulation of FVIII were observed after perioperative FVIII-based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: Due to interindividual variation in desmopressin response, non-severe haemophilia A patients require desmopressin testing prior to therapeutic treatment. However, adequate response or frequency of blood sampling is not standardised in international guidelines. Consequently, various definitions and blood sampling protocols are currently applied. Interestingly, sustainability of desmopressin response is not incorporated into these definitions., Aim: To study desmopressin response rates in a cohort of non-severe haemophilia A patients using currently accepted desmopressin response definitions. This, in order to formulate a standardised, uniform response which includes information on sustainability and to design a standardised blood sampling protocol., Methods: Currently used desmopressin responses in non-severe haemophilia A patients were derived from a literature search. Actual desmopressin response rates were individualised in 105 non-severe HA patients from the Erasmus University Medical Centre and classified according to current varying definitions., Results: Five response definitions were evaluated, three of which included only factor VIII (FVIII):C cut-off levels and two also incorporated FVIII:C-fold increase over baseline., Fviii: C-fold increase showed no association with desmopressin response sustainability., Fviii: C 1 hour after infusion (<0.30, ≥0.30-0.49, ≥0.50-0.79 and ≥0.80 IU/mL) was, however, indicative of desmopressin response after 6 hours., Conclusion: We suggest standardised desmopressin response based on clinically relevant FVIII:C levels, e.g. 0.30 and 0.50 IU/mL. In addition, patients with <0.30 IU/mL FVIII:C after 1 hour (non-responder) or ≥0.80 IU/mL (sustained responder) do not require subsequent blood sampling. However, patients with ≥0.30-0.79 IU/mL FVIII:C after 1 hour should undergo blood sampling after 6 hours to additionally determine response sustainability., (© 2017 John Wiley & Sons Ltd.)

Introduction: von Willebrand disease (VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients., Aim: To investigate whether plasminogen activator inhibitor-1 (PAI-1) level influences the variation in bleeding tendency in VWD patients., Methods: PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score., Results: PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [IQR 12-60] vs. 20 [IQR 10-44] ng mL -1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [IQR 7-17] vs. 9 [IQR 5-14] ng mL -1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: -0.170, P = 0.017) in the group of 196 young (age ≤ 45 year) female VWD patients, accounting for 31% of our study population., Conclusion: In young female VWD patients, we observed that low PAI-1 levels were associated with a higher bleeding score, which may partly explain the observed variability in bleeding phenotype in VWD patients., (© 2017 John Wiley & Sons Ltd.)

Background: Transmural support by a haemophilia nurse may improve treatment and may empower parents and patients., Aim: To measure the effect of structured home visits by a haemophilia nurse in (parents of) patient on aspects of prophylactic home treatment., Methods: A multicentre intervention study in two paediatric haemophilia treatment centres was performed. Primary outcome measures were: adherence to prescribed treatment, health-related quality of life and behavioural scores. Secondary outcome measures were: total clotting factor consumption, self-efficacy and number of joint bleeds., Results: Over a period of 22 months (median, IQR 21-23), four to seven home visits in 46 patients (mean age 9.4 ± 4.2 years) were made. No difference in adherence to prescribed treatment was seen after the home visits when compared to baseline measurements. Both the Child Health Questionnaire (CHQ) scales on 'Role functioning - Emotional/Behavioural' (P = 0.02, d = 0.53) and 'Parental Time Impact' (P = 0.04, d = 0.33) were reduced after intervention. The disease-specific Haemo-QoL questionnaire showed improvement in domains: 'Family' (P = 0.04, d = -0.14), 'Friends' (P = 0.03, d = -0.29) and 'Perceived support' (P = 0.03, d = -0.37). Significant improvement was observed with regard to domain 'Communication' of the VERITAS-Pro scale (P = 0.03, d = -0.28)., Conclusions: After a period of transmural care by a haemophilia nurse, significant but small positive effects were demonstrated with regard to communication and increase of perceived support between parents and haemophilia treatment centre. No improvement was observed in other outcome measures., (© 2016 John Wiley & Sons Ltd.)

Background and Objectives: In mice, loss of sialic acid resulting in shedding of glycoprotein (GP) Ibα and GPV has been linked to platelet survival. The aim of this study was to determine whether loss of sialic acid and the GPIb-IX-V complex contributes to development of the platelet storage lesion (PSL) in human platelet concentrates (PCs)., Materials and Methods: PCs (stored in plasma (with or without Mirasol treatment); PAS-C or PAS-E) were stored at room temperature. Flow cytometry was used to monitor membrane expression of the GPIb-IX-V complex, CD62P, surface glycans and PS exposure. The functionality of stored platelets was determined employing aggregometry and ristocetin-induced VWF binding., Results: Storage time of PCs in blood banks is limited to 7 days. During this time period, a minor but gradually increasing subpopulation of GPIbα-negative platelets was observed. Also, ristocetin-induced VWF binding was impaired in a small population of platelets. Mean surface expression of GPIbα and GPV remained stable until day 9, whereas CD62P expression increased; also a rapid decrease in ADP-induced aggregation was observed for PAS-C, PAS-E and Mirasol-treated PCs. Upon prolonged storage (>9 days), a slow decline in surface expression of GPIbα and GPV was observed; no major changes were observed in surface sialylation with the exception of Mirasol-treated platelets., Conclusion: In a small population of stored platelets, changes in GPIbα occur from day 2 onwards. Loss of sialic acid and subsequent shedding of GPIbα and GPV is not an early event during the development of the PSL., (© 2016 International Society of Blood Transfusion.)

Background: Joint bleeds are reported by 23% of von Willebrand disease (VWD) patients and associated with orthopaedic surgery. Limited data are available on joint surgery in VWD., Aim: To assess the prevalence, indications, management and complications of joint surgery in VWD patients., Methods: 804 VWD patients with historically lowest von Willebrand factor (VWF) activity ≤30 U dL -1 completed a questionnaire on joint bleeds, joint damage and orthopaedic surgery. We retrieved additional medical file data of patients who underwent surgery on large joints (shoulder, elbow, hip, knee or ankle)., Results: 116 out of 804 patients (14%) reported large joint surgery. Compared to VWD patients without previous orthopaedic surgery, these 116 patients reported more frequently a history of joint bleeds and joint damage (41% vs. 20%, P < 0.001 and 61% vs. 20%, P < 0.001). Medical file data on 126 large joint surgeries in 79 VWD patients revealed that this surgery was associated with joint damage due to prior joint bleeds in 24% of the procedures. Preoperative clotting factor correction (CFC) to prevent bleeding was administered in most cases (81%). Documentation on postoperative bleeding was found in 23 surgeries (18%)., Conclusions: Large joint surgery is reported by 14% of VWD patients, related to joint bleeds in 24% and seems associated with bleeding complications frequently despite perioperative CFC., (© 2015 John Wiley & Sons Ltd.)

Introduction: Desmopressin is frequently used in patients with bleeding disorders because of its prohaemostatic effects. In recent years desmopressin use increased due to reported high incidence of inhibitors in mild haemophilia after clotting factor infusion and the rising costs of clotting factor concentrates. The safety and frequency of side effects have hardly been assessed in well-designed studies., Aim: We therefore prospectively evaluated side effects of desmopressin in a large unselected cohort of bleeding disorder patients, who received a desmopressin test dose., Methods: Blood was drawn prior to, one, three, six and 24 h after desmopressin. Primary outcome was change in serum sodium, haematocrit, serum- and urine osmolality, body weight and vital signs. Self-reported side effects were evaluated as secondary outcome., Results: In total, 108 patients were included, median age 30 years, the majority of whom had von Willebrand disease type 1 (76%). A significant change in water balance parameters was observed. Four patients (4%) had hyponatraemia (≤135 mmol L(-1) ) after 24 h but no severe hyponatraemia occurred (≤125 mmol L(-1) ). After infusion, 41 (38%) patients were hypotensive (≤90 mmHg SBP and/or ≤60 mmHg DBP) and 10 (9%) presented with tachycardia (>100 min(-1) ). However, none of these effects sustained at 24 h. Infusion was discontinued in one patient because of tachycardia, nausea and malaise. Self-reported side effects included: headache, fatigue, flush and dizziness., Conclusion: Observed side effects correspond with the known antidiuretic and vasomotor effects of desmopressin. Changes in parameters were temporary and not clinically relevant. In conclusion, our study supports desmopressin use as a safe treatment option in patients with various bleeding disorders., (© 2015 John Wiley & Sons Ltd.)

Introduction: Patients', parents' and providers' preferences with regard to medical innovations may have a major impact on their implementation., Aim: To evaluate barriers and facilitators for individualized pharmacokinetic (PK)-guided dosing of prophylaxis in haemophilia patients, parents of young patients, and treating professionals by discrete choice experiment (DCE) questionnaire., Patients/methods: The study population consisted of patients with haemophilia currently or previously on prophylactic treatment with factor concentrate (n = 114), parents of patients aged 12-18 years (n = 19) and haemophilia professionals (n = 91). DCE data analysis was performed, taking preference heterogeneity into account., Results: Overall, patients and parents, and especially professionals were inclined to opt for PK-guided dosing of prophylaxis. In addition, if bleeding was consequently reduced, more frequent infusions were acceptable. However, daily dosing remained an important barrier for all involved. 'Reduction of costs for society' was a facilitator for implementation in all groups., Conclusions: To achieve implementation of individualized PK-guided dosing of prophylaxis in haemophilia, reduction of bleeding risk and reduction of costs for society should be actively discussed as they are motivating for implementation; daily dosing is still reported to be a barrier for all groups. The knowledge of these preferences will enlarge support for this innovation, and aid in the drafting of implementable guidelines and information brochures for patients, parents and professionals., (© 2015 John Wiley & Sons Ltd.)

Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are <0.50 IU mL(-1) , prophylactic treatment is indicated and administered according to international guidelines. However, optimal dose and duration are unknown and bleeding may still occur. The aim of this study was to investigate the outcome in women with von Willebrand disease (VWD) or haemophilia carriership treated according to current practice guidelines. From the period 2002-2011, 185 deliveries in 154 VWD women or haemophilia carriers were retrospectively included. Data on blood loss, bleeding disorder characteristics and obstetric risk factors were obtained. The outcome was primary PPH, defined as blood loss ≥500 mL within 24 h postpartum and severe PPH as blood loss ≥1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL(-1) cut-off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2-6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population., (© 2015 John Wiley & Sons Ltd.)

Background: Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown., Objectives: The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD., Methods: In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1)] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB., Results: Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05) compared to VWD patients not reporting JB. Of 55 patients with available JB data, 65% had the first JB before age 16. These 55 patients used more clotting factor concentrate (CFC; median dose 43 vs. 0 IE FVIII kg(-1) year(-1) , P < 0.001), more often had X-ray joint damage (44% vs. 11%, P = 0.001] and chronic joint pain (44% vs. 18%, P = 0.008) compared to 55 control VWD patients without JB., Conclusion: In conclusion, joint bleeds are reported by 23% of moderate and severe VWD patients, mostly start in childhood, are associated with more CFC use, joint pain, lower HR-QoL and significantly more radiological and self-reported joint damage., (© 2015 John Wiley & Sons Ltd.)

Treatment adherence in haemophilia is strongly associated with quality of life and the cost-benefit of treatment. Therefore, it is important to quantify and monitor it. This study aimed to validate a translation of the VERITAS-Pro cross-culturally and analyse treatment adherence in a Dutch population of paediatric haemophilia patients. Children aged 1-18 years with haemophilia were included from three Haemophilia Treatment Centres, on prophylactic clotting factor replacement therapy for more than 1 year. Parents and adolescents were analysed separately. The adherence scale for prophylactic therapy (VERITAS-Pro) was translated according to international guidelines. This instrument contains a total of six subscales ('Time', 'Dose', 'Plan', 'Remember', 'Skip' and 'Communicate') each with four items. Lower scores reflect higher adherence. Overall response rate was 85%, leading to a study population of 60 children. Mean age was 10 years (SD 4.1). Internal consistency reliability: Mean Cronbach's alphas were adequate (>0.70) for total score and the subscales 'Skip' and 'Communicate'. Item-own subscale correlations were stronger than most item-other subscale correlations. Convergent validity: Total scores were higher for non-adherent participants compared with adherent participants according to patient infusion logs (n = 48; P < 0.05). Test-retest correlations: Significant for all scales except 'Dose' (n = 58; P < 0.01). This study demonstrates applicability of VERITAS-Pro outside the United States, as total score and most subscales effectively quantified treatment adherence in a Dutch paediatric population on prophylactic therapy. Non-adherent respondents' total scores were significantly higher, demonstrating the ability of VERITAS-Pro to identify non-adherent individuals., (© 2014 John Wiley & Sons Ltd.)

Higher self-efficacy in chronic disease patients is associated with higher development of self-management skills and increased quality-of-life. Quantification and monitoring of self-efficacy is therefore of importance. Self-efficacy in haemophilia patients has received little attention due to lack of standardized scales. To validate the novel Haemophilia-specific Self-Efficacy Scale (HSES) in haemophilia patients on prophylactic home treatment, haemophilia patients aged 1-18 years on prophylactic treatment ≥1 year were included from three Dutch Haemophilia Treatment Centres. The HSES consists of 12 items, relating to perceptions of the ability to function on a day-to-day basis with regard to patient's disease. Retest was performed in a subsample. Validity was proven by the General Self-Efficacy Scale and by the health-related quality-of-life assessment tool Haemo-QoL. Data were analysed from 53 children (response 75%), with a mean age of 9.8 years (SD 4.0). Mean total scale score of HSES was 55.5 (SD 4.7; range 38-60), with a ceiling effect of 17%. The HSES showed adequate internal consistency (Cronbach's alpha 0.72) and good test-retest reliability (Intra-Class-Correlation coefficient 0.75; P < 0.01; n = 37). The convergent validity was adequate as haemophilia-specific self-efficacy correlated significantly with general self-efficacy (r = 0.38; P < 0.01). High HSES scores correlated significantly with quality-of-life as measured by the Haemo-QoL (r = -0.42; P ≤ 0.01). The novel HSES is a reliable and valid tool to assess self-efficacy in paediatric haemophilia patients on prophylactic home treatment. High self-efficacy correlated with higher quality-of-life, further underlining the importance to standardly assess, monitor and improve self-efficacy., (© 2014 John Wiley & Sons Ltd.)

The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥ 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious., (© 2012 Blackwell Publishing Ltd.)

Home treatment of haemophilia is currently the standard of care for patients with severe haemophilia. Home treatment increases the responsibility of the patients for their own treatment and care. Therefore, it is of utmost importance to attain a high level of knowledge and practical skills. The aim of our study was to investigate whether or not an educational e-learning program improves knowledge and skills of adult patients with haemophilia on home treatment. Participants treated at the Haemophilia Treatment Center of the Erasmus University Medical Centre completed a questionnaire to test their knowledge of haemophilia, treatment of bleedings and of complications of treatment and were observed during the intravenous injection of clotting factor concentrate, using a standardized scoring list. Afterwards they were randomized to follow an e-learning program or no intervention (control group). After 1 month they completed the same questionnaire again and practical skills were scored once more. At baseline, haemophilia patients (n = 30) scored 24 of 48 questions in the questionnaire correctly. Seventy-five per cent of the items on the practical skills scoring list were performed correctly. One month later, the e-learning group (n = 16; 36; 18-45) showed a higher level of theoretical knowledge compared to the control group (n = 14; 26; 19-32; P < 0.001). Also practical skills were significantly better in the group that followed the e-learning program compared to the control group (respectively P = 0.002). Self-efficacy of 90% vs. 80% the patients with haemophilia was high in all patients. Our study shows that in haemophilia patients with haemophilia, who are on home treatment, knowledge of haemophilia treatment and complications as well as practical skills can be improved by an educational e-learning program., (© 2012 Blackwell Publishing Ltd.)

Patients with von Willebrand disease (VWD), the most common inherited bleeding disorder, display large variation in bleeding tendency, which is not completely related to VWF levels. The cause of variability in clinical expression is largely unknown. The effect of plasma fibrinolytic capacity on bleeding tendency in VWD patients has not been investigated. We hypothesized that enhanced fibrinolysis may result in a more severe bleeding phenotype. Therefore, we measured the fibrinolytic potential in patients with moderate or severe VWD to investigate the contribution of fibrinolysis to the bleeding tendency. Fibrinolytic potential was measured as plasma clot lysis time (CLT) with and without addition of potato carboxypeptidase inhibitor (PCI) in 638 patients with moderate or severe VWD who participated in a nationwide multicentre cross-sectional study. Bleeding severity was measured using the Bleeding Score (BS).The CLTs were significantly longer, indicative of hypofibrinolysis, in men compared to women with VWD [106.2 (IQR 95.7-118.1) vs. 101.9 (IQR 92.8-114.0) min]. The CLTs prolonged with increasing age. No association was found between VWF or FVIII levels and CLT, or between VWF or FVIII levels and CLT(+PCI) . No association was observed for BS in a model with 10log-transformed CLT, adjusted for age, gender, VWF:Act and FVIII [b = 6.5 (95%CI -0.3 to 13.4)]. Our study showed that the plasma fibrinolytic potential does not influence bleeding tendency in VWD patients and therefore does not explain the variability in bleeding phenotype in VWD., (© 2011 Blackwell Publishing Ltd.)

Three patients with mild haemophilia A who developed high-titre antibodies against factor VIII at high age are reported. These patients had only a limited number of exposure days of FVIII concentrates in the past. The patients had to undergo surgery or presented with recurrent bleeding episodes. Treatment with recombinant FVIIa (rFVIIa) was effective and safe. Despite the high age and the presence of coronary heart disease in one of the patients, no adverse events or thrombotic complications occurred. These cases illustrate that the physician should always be alert on the development of inhibitors, also in elderly patients with mild haemophilia, in whom FVIII inhibitors had never been detectable before and that treatment with rFVIIa was effective and well-tolerated.

AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT, were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe.

We have prospectively monitored treatment of haemophilia patients with inhibitors by recombinant factor VIIa (rFVIIa) administered by continuous infusion to obtain more insight in the underlying factors of the clinical efficacy of this administration method. At present, 43 treatment episodes of 14 different Dutch haemophilia inhibitor patients are included in the database. Analysis of the data showed a discrepancy between the efficacy of rFVIIa continuous infusion treatment of acute and surgical bleeds in the oral cavity [one (14%) effective, two (29%) partially effective, four (57%) not effective] and other parts of the body [29 (80%) effective, four (11%) partially effective, two (6%) not effective, one (3%) impossible to classify]. Patients who had acute or surgical oral cavity bleeds, uncontrolled by rFVIIa continuous infusion, reacted favourably to rFVIIa continuous infusion in other locations of the body. Acute bleeding episodes in the oral cavity, which could not be controlled by rFVIIa continuous infusion, stopped when the treatment regimen was switched to rFVIIa bolus injections. Finally, haemostatic control during dental extractions was excellent after the initial rFVIIa bolus injection preceding the continuous infusion, but rebleeds occurred in all patients within 48 h under rFVIIa continuous infusion coverage. These observations suggest that the efficacy of rFVIIa continuous infusion depends, at least in part, on the location of the body in which the bleeding occurs and that rFVIIa bolus injections are more effective than rFVIIa continuous infusion in the oral cavity. We hypothesize that the inability of rFVIIa continuous infusion treatment to sufficiently inhibit fibrinolysis is the underlying cause of the decreased efficacy of rFVIIa continuous infusion treatment in the oral cavity.