Johanna G. van der Bom

Factor VIII Products and Inhibitor Development in Severe Hemophilia A

BACKGROUND For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).

F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Hysterectomy and sexual wellbeing: prospective observational study of vaginal hysterectomy, subtotal abdominal hysterectomy, and total abdominal hysterectomy

Abstract Objectives To compare the effects of vaginal hysterectomy, subtotal abdominal hysterectomy, and total abdominal hysterectomy on sexual wellbeing. Design Prospective observational study over six months. Setting 13 teaching and non-teaching hospitals in the Netherlands. Participants 413 women who underwent hysterectomy for benign disease other than symptomatic prolapse of the uterus and endometriosis. Main outcome measures Reported sexual pleasure, sexual activity, and bothersome sexual problems. Results Sexual pleasure significantly improved in all patients, independent of the type of hysterectomy. The prevalence of one or more bothersome sexual problems six months after vaginal hysterectomy, subtotal abdominal hysterectomy, and total abdominal hysterectomy was 43% (38/89), 41% (31/76), and 39% (57/145), respectively (χ2 test, P = 0.88). Conclusion Sexual pleasure improves after vaginal hysterectomy, subtotal abdominal hysterectomy, and total abdominal hysterectomy. The persistence and development of bothersome problems during sexual activity were similar for all three techniques.

A randomised controlled trial comparing abdominal and vaginal prolapse surgery: effects on urogenital function

Objective  To compare the effects of vaginal hysterectomy (combined with anterior and/or posterior colporraphy) and abdominal sacro‐colpopexy (with preservation of the uterus) on urogenital function.

The role of donor antibodies in the pathogenesis of transfusion-related acute lung injury: a systematic review

BACKGROUND: The majority of cases of transfusion‐related acute lung injury (TRALI) are thought to be caused by the presence of leukocyte antibodies in the blood of the donor. We performed a systematic search of the literature to quantify the contribution of donor antibodies to the occurrence of TRALI.

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Trigger Factors and Their Attributable Risk for Rupture of Intracranial Aneurysms: A Case-Crossover Study

Background and Purpose— Little is known about activities that trigger rupture of an intracranial aneurysm. Knowledge on what triggers aneurysmal rupture increases insight into the pathophysiology and facilitates development of prevention strategies. We therefore aimed to identify and quantify trigger factors for aneurysmal rupture and to gain insight into the pathophysiology. Methods— During a 3-year period, 250 patients with aneurysmal subarachnoid hemorrhage completed a structured questionnaire regarding exposure to 30 potential trigger factors in the period soon before subarachnoid hemorrhage (hazard period) and for usual frequency and intensity of exposure. We assessed relative risks (RR) of rupture after exposure to triggers with the case-crossover design comparing exposure in the hazard period with the usual frequency of exposure. Additionally, we calculated population-attributable risks. Results— Eight triggers increased the risk for subarachnoid hemorrhage: coffee consumption (RR, 1.7; 95% CI, 1.2–2.4), cola consumption (RR, 3.4; 95% CI,1.5–7.9), anger (RR, 6.3; 95% CI, 4.6–25), startling (RR, 23.3; 95% CI, 4.2–128), straining for defecation (RR, 7.3; 95% CI, 2.9–19), sexual intercourse (RR, 11.2; 95% CI, 5.3–24), nose blowing (RR, 2.4; 95% CI, 1.3–4.5), and vigorous physical exercise (RR, 2.4; 95% CI, 1.2–4.2). The highest population-attributable risks were found for coffee consumption (10.6%) and vigorous physical exercise (7.9%). Conclusions— We identified and quantified 8 trigger factors for aneurysmal rupture. All triggers induce a sudden and short increase in blood pressure, which seems a possible common cause for aneurysmal rupture. Some triggers are modifiable, and further studies should assess whether reduction of exposure to these factors or measures preventing sudden increase in blood pressure decrease the risk of rupture in patients known to have an intracranial aneurysm.

Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature

There is considerable variability in bleeding patterns of severe haemophilia (<1% factor VIII). Knowledge of the contribution of thrombophilic factors in these patterns may improve individually tailored treatment strategies. We reviewed the literature regarding the relation between prothrombotic factors and clinical phenotype of severe haemophilia. Medline and EMBASE were searched for relevant articles. 9369 articles published between 1963 and September 2003 were screened and seven relevant papers were retrieved. Each of these reported on a different combination of thrombophilic factors. Presence of the factor V Leiden mutation appears to decrease the severity of severe haemophilia most consistently. Findings on other thrombophilic factors were inconclusive. There is a clear need for additional research on potential determinants of phenotypes of severe haemophilia before such knowledge can be translated into individual care for severe haemophilia patients with confidence.

Effects of euthanasia on the bereaved family and friends: a cross sectional study

Abstract Objective To assess how euthanasia in terminally ill cancer patients affects the grief response of bereaved family and friends. Design Cross sectional study. Setting Tertiary referral centre for oncology patients in Utrecht, the Netherlands. Participants 189 bereaved family members and close friends of terminally ill cancer patients who died by euthanasia and 316 bereaved family members and close friends of comparable cancer patients who died a natural death between 1992 and 1999. Main outcome measures Symptoms of traumatic grief assessed by the inventory of traumatic grief, current feelings of grief assessed by the Texas revised inventory of grief, and post-traumatic stress reactions assessed by the impact of event scale. Results The bereaved family and friends of cancer patients who died by euthanasia had less traumatic grief symptoms (adjusted difference −5.29 (95% confidence interval −8.44 to −2.15)), less current feeling of grief (adjusted difference 2.93 (0.85 to 5.01)); and less post-traumatic stress reactions (adjusted difference −2.79 (−5.33 to −0.25)) than the family and friends of patients who died of natural causes. These differences were independent of other risk factors. Conclusions The bereaved family and friends of cancer patients who died by euthanasia coped better with respect to grief symptoms and post-traumatic stress reactions than the bereaved of comparable cancer patients who died a natural death. These results should not be interpreted as a plea for euthanasia, but as a plea for the same level of care and openness in all patients who are terminally ill.