Psychometrics of patient-reported outcomes measurement information system in von Willebrand disease, inherited platelet function disorders, and rare bleeding disorders.

Background: Patient-reported outcomes measurement information system (PROMIS) measures can be used to measure patient-reported outcomes. PROMIS measures, including computer adaptive tests (CATs) and short forms, have demonstrated the ability to adequately assess outcomes in patients with hemophilia. It is, however, unclear if PROMIS measures are suitable for patients with von Willebrand disease (VWD), inherited platelet function disorders (IPFDs), and rare bleeding disorders (RBDs). Objectives: To evaluate the feasibility, measurement properties, and relevance of PROMIS measures in adults with VWD, IPFDs, and RBDs. Methods: In this cross-sectional multicenter study, adults with VWD, IPFDs, and RBDs completed 9 PROMIS measures and the Short Form-36 version 2 (SF-36v2) electronically. Feasibility was determined by the number of completed items and floor/ceiling effects. Measurement properties included construct validity based on a multitrait-multimethod analysis and reliability using the reliability coefficient and greatest lower bound. Relevance was evaluated based on comparison with the Dutch general population. Results: In total, 111 patients (median age, 57 years [IQR, 44-67]; 60% VWD, 16% IPFD, 24% RBD) participated. Mean number of items answered varied from 5.3 to 8.7 (range, 4-12) per PROMIS CAT in patients with VWD. Construct validity was supported for all CATs and all instruments had a good reliability (≥0.70). The PROMIS measures had less ceiling effects than the SF-36v2. Conclusion: The PROMIS measures are a feasible, valid, and reliable alternative for the SF-36v2 in patients with primarily nonsevere forms of VWD. The relevance of the selected measures was limited. Additional research is necessary to evaluate the PROMIS measures in adults with IPFDs and RBDs.

Efficacy of a 1:1 ratio VWF/FVIII concentrate in patients with von Willebrand disease.

INTRODUCTION: Patients with von Willebrand disease (VWD) require administration of von Willebrand factor (VWF) concentrates peri-operatively. Concerns about FVIII accumulation after repetitive injections of a 1:1 ratio VWF/FVIII clotting factor concentrate (CFC) led this study to explore the recovery and FVIII accumulation over time. METHODS: This monocentre study examined patients with VWD receiving perioperative 1:1 ratio CFC infusions. CFC dosing was based on body weight and endogenous VWF/FVIII activity. FVIII and VWF activity was monitored at T0 (baseline), T1 (15 min postinfusion), and trough levels at T2-T6 (24-120 h). RESULTS: We included 125 patients, undergoing 125 procedures (63 major surgeries, 62 minor), with a median of two CFC infusions (IQR 1-3). With a mean administered dose of 35.7 IU/kg CFC, recovery rates of FVIII and VWF were 2.6 IU/dL per IU/kg and 2.4 IU/dL per IU/kg, respectively. Mean FVIII levels at T0 were 62 (SD 51.9), T1: 164 (SD 80.4), T2: 155 (SD 62.8), T3: 162 (SD 59.8), T4: 124 (SD 78.4), and T5: 120 (SD 65.3) IU/dL. Mean VWF activity levels at T0 were 29 (SD 25.0), T1: 133 (SD 43.7), T2: 92 (SD 37.2), and T3: 86 (SD 37.5) IU/dL. Subgroup analysis in 47 patients with more than three infusions, showed no accumulation of mean FVIII levels. CONCLUSION: This perioperative study demonstrated excellent FVIII and VWF recovery of a 1:1 ratio VWF product in patients with VWD. Stable FVIII and VWF activity levels were observed after repeated infusions, without accumulation. Most major surgeries required only three CFC infusions.

Familial Male-limited Precocious Puberty (FMPP) and Testicular Germ Cell Tumors.

OBJECTIVE: The purpose of this study is to report development of a malignant testicular germ cell tumor (GCT) in 2 young adult males with familial male-limited precocious puberty (FMPP) because of LHCGR pathogenic variants in 2 families. Secondarily, to study the possible relation between FMPP and testicular tumors and to investigate whether FMPP might predispose to development of malignant testicular tumors in adulthood a literature review is conducted. METHODS: Data on 6 cases in 2 families are obtained from the available medical records. In addition, a database search is performed in Cochrane, PubMed, and Embase for studies that report on a possible link between FMPP and testicular tumors. RESULTS: The characteristics of 6 males with FMPP based on activating LH receptor (LHCGR) germline pathogenic variants are described, as are details of the testicular GCTs. Furthermore, a literature review identified 4 more patients with signs of FMPP and a (precursor of) testicular GCT in adolescence or adulthood (age 15-35 years). Additionally, 12 patients with signs of precocious puberty and, simultaneously, occurrence of a Leydig cell adenoma or Leydig cell hyperplasia are reported. CONCLUSION: There is a strong suggestion that FMPP might increase the risk of development of testicular GCTs in early adulthood compared with the risk in the general population. Therefore, prolonged patient monitoring from mid-pubertal age onward including instruction for self-examination and periodic testicular ultrasound investigation in patients with a germline LHCGR pathogenic variant might contribute to early detection and thus early treatment of testicular GCT.

Prevalence, burden and treatment effects of vaginal bleeding in women with (suspected) congenital platelet disorders throughout life: a cross-sectional study.

Congenital platelet disorders (CPDs) are rare bleeding disorders that are associated with mucocutaneous bleeds. However, data on vaginal bleeding in women with CPDs are scarce. A set of generic and bleeding-specific questionnaires were used to evaluate the prevalence of vaginal bleeding, its impact on quality of life (QoL) and sexual functioning and the consequences for pregnancy, miscarriage and delivery in a cohort of women who were referred for diagnostic evaluation for CPDs. A total of 78 women included in the study were either diagnosed with a CPD (n = 35) or were clinically suspected of a CPD (n = 43). Heavy menstrual bleeding (HMB) was reported by a large proportion of women, which mainly started at menarche. In all, 76% of women received any kind of HMB treatment, often leading to surgical prodecures. HMB was shown to have a high impact on QoL, which improved upon treatment. Even though women reported that vaginal bleeding affects sexuality, this topic is not frequently discussed with physicians. Heavy blood loss frequently occurred after miscarriage/delivery, often requiring treatment. Women with (suspected) CPDs frequently encounter HMB, negatively impacting daily life and sexual functioning. Together with peripartum bleeding, these data highlight the burden of vaginal bleeding in CPDs and importance of adequate treatment.

Menstrual and obstetrical bleeding in women with inherited platelet receptor defects-A systematic review.

INTRODUCTION: Women with inherited platelet receptor defects (IPRD) may have an increased risk of heavy menstrual bleeding (HMB) and postpartum haemorrhage (PPH). AIM: To present a systematic overview of the literature on the prevalence and management of menstrual and obstetrical bleeding in women with IPRD. METHODS: Electronic databases were searched for original patient data on the prevalence and management of HMB and PPH in women with known IPRD or who were being investigated for IPRD. RESULTS: Sixty-nine papers (61 case reports/series and 8 cohort studies) were included. Overall, studies were rated as 'poor quality'. The included cohort studies reported HMB in 25% (13/52) of women with Bernard-Soulier syndrome and in 22.1% (34/154) of women with Glanzmann thrombasthenia. In total, 164 deliveries in women with IPRD were described. Excessive bleeding occurred in 16.9% (11/65) of deliveries described in the largest cohort. PPH occurred in 63.2% (55/87) of deliveries described in case reports/series. PPH occurred in 73.7% (14/19) of deliveries that were not covered by prophylaxis compared with 54.2% (32/59) of deliveries that were (OR = 2.36, 95% CI 0.75-7.40). Neonatal bleeding complications were reported in 10.0% (8/80) of deliveries. In all (6/6) deliveries with neonatal bleeding complications wherein the presence of alloantibodies was investigated, either antiplatelet or anti-HLA antibodies were detected. DISCUSSION/CONCLUSION: Menstrual and particularly obstetrical bleeding problems frequently occur in women with IPRD, based on small case reports and series of poor quality. International collaboration, preferably on prospective studies, is needed to improve clinical management of women-specific bleeding in IPRD.

Potential for glomerular C4d as an indicator of thrombotic microangiopathy in lupus nephritis.

OBJECTIVE: In patients with systemic lupus erythematosus (SLE) and lupus nephritis, the presence of antiphospholipid antibodies (aPL) is considered to be an indication of increased risk of thrombotic microangiopathy, a serious complication of SLE. Previous studies have demonstrated a critical role for activation of the classical pathway of complement that leads to thrombotic injury in the presence of aPL. This study was undertaken to investigate whether C4d deposition in lupus nephritis is related to circulating aPL and the presence of renal microthrombi. METHODS: Deposition patterns of C4d in 44 renal biopsy samples obtained from 38 patients with biopsy-proven lupus nephritis were determined by staining with a polyclonal anti-C4d antibody. A phosphotungstic acid-hematoxylin stain was used to identify fibrin microthrombi. Clinical data (serum creatinine levels and presence or absence of aPL) were obtained and correlated with findings in the renal biopsy specimens. Patients were categorized as having aPL (n = 20) or not having aPL (n = 18). RESULTS: A strong relationship between the intensity of glomerular C4d staining and the presence of microthrombi was found (P < 0.002). Intense glomerular C4d deposition was present in 7 of 8 biopsy samples showing renal microthrombi. Neither C4d deposition nor the presence of microthrombi was correlated with aPL status. CONCLUSION: Our findings suggest that activation of the classical pathway of complement plays a pathogenic role in the development of renal tissue injury leading to thrombosis, irrespective of the type of circulating antibodies present. Immunodetection of glomerular C4d deposition in renal biopsy samples could be a convenient method of identifying patients at risk of thrombotic microangiopathy.

Chimerism occurs in thyroid, lung, skin and lymph nodes of women with sons.

Chimerism indicates the presence of cells from one individual in another. Pregnancy and blood transfusions are considered the main sources for chimerism. Chimeric cells have been attributed a pathogenic role in various autoimmune diseases. However, data on the occurrence of chimeric cells in normal organs are scarce. In order to gain insight into the possible pathogenic potential of chimeric cells in autoimmune disease, it is necessary to determine the prevalence of chimeric cells in organs not affected by autoimmune disease. In situ hybridization for the Y-chromosome was performed on organs obtained at autopsy of 51 women. We investigated 44 thyroid, 38 lung, 21 skin and 7 lymph node samples. All women had sons, and data from their blood transfusion histories were retrieved for at least 10 years before death. Slides were scored semi-quantitatively for chimerism as low (1-3 Y-chromosome-positive cells per slide), moderate (4-10 positive cells per slide) or high (more than 10 positive cells per slide). Y-chromosome-positive cells were found in 8 thyroid, 10 lung, 3 skin and 1 lymph node samples of 18 women. There was no association between the presence of chimeric cells and blood transfusion history. Most organs in which chimerism was present contained a small to moderate level. Thus, chimerism can occur in normal organs of women without autoimmune disease. Our results indicate that chimerism is not necessarily associated with disease.

Tissue chimerism in systemic lupus erythematosus is related to injury.

BACKGROUND: Chimerism indicates the presence of cells from one individual in another individual, and has been associated with several autoimmune diseases. Although this finding may point towards a role for chimerism in the induction of SLE, it could also indicate that chimerism is the result of repair mechanisms after injury. OBJECTIVE: To perform a post-mortem investigation for the presence of chimerism in 48 organs from seven women with SLE and establish whether there was a relationship between chimerism and injury. METHODS: Chimeric male cells in female tissue specimens were identified by in situ hybridisation of the Y-chromosome. Organs were categorised into four different groups according to injury experienced. RESULTS: were compared with those for unaffected control organs. Results: Chimerism was found in all seven patients with SLE. Y-chromosome-positive cells were present in 24 of 48 organs from women with SLE, which was significantly more than in control organs (p<0.001). Chimerism occurred more often in organs from patients with SLE who had experienced injury than in normal control organs, irrespective of whether the injury experienced was SLE-related, non-SLE-related or both. CONCLUSIONS: This is the first report of the distribution of chimerism in a large number of organs from women with SLE. It shows that the occurrence of chimerism is related to injury. The data support the hypothesis that tissue chimerism is the result of a repair process.

Chimerism occurs twice as often in lupus nephritis as in normal kidneys.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an immune-mediated disease that particularly affects the kidneys, causing lupus nephritis. In experimental mouse models, lupus nephritis can be mimicked by inducing a chimeric state through the injection of parental T cells in offspring. In humans, pregnancy-induced chimerism may play a role in the pathogenesis of autoimmune diseases such as SLE, but it is likely that only certain chimeric cells have pathogenic potential. In this study, we investigated whether the distribution of chimeric cells is different in the kidneys of women with SLE from that in normal kidneys, and we examined the phenotype of chimeric cells in women with SLE. METHODS: The presence of chimeric cells was investigated by in situ hybridization targeting the Y chromosome in 57 renal biopsy samples from 49 women with lupus nephritis. Fifty-one kidney autopsy specimens without histomorphologic lesions served as controls. Double-staining for the Y chromosome in combination with CD3 and CD34 markers was performed in 5 kidney specimens with lupus nephritis to identify the phenotype of the chimeric cells. RESULTS: Y chromosome-positive cells were found in 27 of 49 patients with lupus nephritis and in 13 of 51 normal controls (P < 0.01). Both CD3+ and CD34+ chimeric cells were identified in lupus nephritis kidney specimens. CONCLUSION: Chimeric cells are present significantly more often in kidneys with lupus nephritis than in normal kidneys, and some of these chimeric cells are T cells. This finding is interesting in light of experimental models demonstrating that lupus nephritis is initiated by chimeric T cells.

Endothelial chimerism in transplantation: Looking for needles in a haystack.

Endothelial chimerism in transplanted organs is a fascinating phenomenon, indicative of a mechanism by which progenitor recipient cells replace the donor endothelium. It has been hypothesized that this replacement could lead to a decrease in alloreactivity and thus would positively influence graft outcome. However, recent studies have shown that the amount of recipient-derived endothelial cells found in donor organs is relatively small. What effect on graft survival can we expect from this low number of chimeric cells? There are several hypotheses that address this question, but distinguishing the true effect of donor endothelial replacement on outcome from other factors affecting graft survival is difficult. Furthermore, "contamination" of chimeric cells from sources other than the recipient would have to be excluded before the effect of donor endothelial replacement by recipient cells can be accurately assessed. Pregnancies and blood transfusions are the other sources that may induce chimerism. Most of the techniques currently used to detect chimeric cells in donor organs are not specific enough to distinguish chimeric cells that may have been present in the graft before transplantation and recipient-derived chimeric cells that replace the endothelium after transplantation. Also, the sensitivity of these techniques may be questioned: do we really detect all chimeric cells that are present? This review will elaborate on these questions and discuss future perspectives of research into chimerism.

Chimerism in kidneys, livers and hearts of normal women: implications for transplantation studies.

Tissue chimerism was recently described in transplanted organs from female donors into male recipients, by demonstration of the Y-chromosome in tissue-derived cells. It was claimed that these Y-chromosome positive cells were recipient derived. To find out whether the chimeric cells, derived from pregnancies of sons or blood transfusions, could have been present in the solid organs before transplantation, we performed the following study. In situ hybridization for the Y-chromosome was performed on the normal organs (51 kidneys, 51 livers, 69 hearts) from 75 women of the normal population, whose child and blood transfusion status were known. Chimeric cells were found in 13 kidneys, 10 livers and 4 hearts, of 23 women. There was no relation between the child status or the blood transfusion history with the presence of Y-chromosome positive cells. We have for the first time demonstrated that male cells are present in normal kidneys, livers and hearts. Theoretically, these organs could have been used for the transplantation. Therefore, our findings demonstrate that the chimeric cells thus far described in transplantation studies, are not necessarily donor derived, and could have been present in the organs before the transplantation.