Difference In Bleeding Score Research Articles

Acquired Hemophilia a: A Single-Center Study of 165 Patients

Introduction and aim: Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by the existence of factor VIII (FVIII) inhibitors with an estimated annual incidence of 1.5 per million people. AHA patients are characterized by exceeding bleeding of varying severity, while approximately 10% of AHA patients have no bleeding symptoms. It's a challenge to diagnose and manage AHA due to its rarity and heterogeneity. We conducted a retrospective study to report the characteristics and outcomes of AHA and enhance its recognition and management. Methods: Patients diagnosed and treated with AHA at the Blood Disease Hospital, Chinese Academy of Medical Sciences between July 1997 to December 2021 were retrospectively enrolled. Demographics, clinical characteristics, treatments, and outcomes were collected. All Patients were followed immediately from admission to our center and ended in March 2022. Bleeding severity was assessed retrospectively in March 2022 by bleeding score (BS), a summary score aggregated by the International Society on Thrombosis and Hemostasis/ Scientific and Standardization Committee (ISTH/SSC) bleeding assessment tool (BAT) (2010 edition). Results: A total of 165 AHA patients admitted to our center were enrolled. The median age at diagnosis was 45 (10-90) years. Overall, a female preponderance (106/165, 64.2%) was observed in this cohort. Notable, the proportion of male patients increased with age. Most patients (126/165, 76.4%) were idiopathic with no underlying diseases discovered. Of the 39 (23.6%) patients with associated diseases, 12 patients had autoimmune diseases, 16 patients had infections, eight patients had malignancies (all solid tumors) and three patients were secondary to pregnancy. All patients presented at least one bleeding episode. Subcutaneous bleeding was most common affecting 84.8% (140/165) of patients, while hemarthrosis was infrequent (n=11, 6.7%). The median time from bleeding to be diagnosed as AHA was delayed (30, 2-5650 days). Anti-FVIII antibody titer and FVIII level showed no correlation. A significant difference in FVIII activity was observed between patients with anti-FVIII antibody titer < 20 BU/ml and ≥ 20 BU/ml. The BS varied among all patients ranging from 2 to 12 with a median of 4. A significant difference in BS was observed among the mild (FVIII: C > 5 IU/dl), moderate (1 IU/dl < FVIII: C ≤ 5 IU/dl), and severe (FVIII: C ≤ 1 IU/dl) AHA patients (p < 0.05). The same conclusion was also drawn between patients with low anti-FVIII antibody titer (< 20 BU/ml) and high antibody titer (≥ 20 BU/ml). BS was not correlated with APTT (r=0.-0.04, 95% CI (-0.19-0.12), p > 0.05). Hemostatic treatment was applied to 129 (78.2%) AHA patients. Of the 163 patients who received immunosuppressive therapy (IST), 22 (13.5%) received steroids alone, with an 82.4% complete remission (CR) rate, 50 (30.7%) received steroids plus cyclophosphamide (CTX), with an 85.0% CR rate, 80 (49.1%) received rituximab-based therapy, which includes rituximab plus steroids, rituximab plus steroids and CTX, and rituximab plus steroids and other immunosuppressants, with a 93.3% CR rate (Figure 1A). There were seven deaths. Causes of death were bleeding (n=3), underlying disease (n=1), pulmonary infection (m=1), and unknown (n=2). FVIII inhibitor titer ≥ 20 BU/ml was the only significant poor prognostic factor for CR (HR 0.56; 95% CI, 0.37-0.85; p < 0.01). In addition, patients with FVIII inhibitor titers ≥ 20 BU/ml needed more time to achieve CR (130 days vs. 35 days; p < 0.01) and showed a lower CR rate (77.6% vs. 94.9%, p < 0.01) than those with FVIII inhibitor titers < 20 BU/ml (Figure 1B). Conclusions: Delayed diagnosis of AHA patients is a severe issue. The rituximab-based regimen is more likely to achieve a CR in AHA patients. The only poor predictor of CR for AHA patients was FVIII inhibitor titer ≥ 20 BU/ml.

Efficacy of gelatamp in controlling the postoperative sequelae following mandibular posterior teeth extraction - A split-mouth study.

This study aimed to evaluate the effectiveness of gelatamp on soft tissue healing, bleeding, and pain following mandibular posterior teeth extraction. This study was designed as a split-mouth, prospective randomized double-blind controlled trial conducted in a single tertiary care center. Thirty-five subjects indicated for routine mandibular posterior teeth extraction were divided into two groups using the lottery technique: the experimental group (n=30), which received gelatamp after extraction, and the control group (n=30), which received no intervention. The primary outcomes included soft tissue healing(Landry, Turnbull, Howley index) and Pain(VAS score). The secondary outcomes assessed were bleeding(Maani et al. index) and swelling(Sauza and Consone assessment). The results showed a statistically significant difference in soft tissue healing on the third and seventh days in the experimental group (p≤0.05) than in the control group. A significant difference in bleeding scores at 5min, 30min, and 2h postoperatively in the study group (p≤0.05) was noted. There was no significant difference between the groups for pain on the first, third or seventh day postoperatively (p≤0.05). The swelling assessment also showed no significant changes (p=0.831) for the study and the control group. Based on the findings of this study, gelatamp can be effectively used to reduce postoperative sequelae such as bleeding with better soft tissue healing following extractions and surgical removal of tooth.

The Reproducibility of Treatment of Perimenopausal Abnormal Uterine Bleeding Due to Ovulatory Dysfunction with Hysteroscopic Endometrial Resection versus Mirena

Objective: To compare the efficacy of local levonorgestrel intrauterine releasing system and transcervical resection of the endometrium (TCER) in the management of perimenopausal dysfunctional uterine bleeding. Patients and Methods: This study was done at Ain Shams and Al-Azhar University Maternity Hospitals during a period started from January 2019 to January 2021. Patients were followed up at the outpatient gynaecology clinics at regular schedules (3, 6 and 12 months) for one year duration. Perimenopausal patients with DUB were assigned randomly to either the levonorgestrel intrauterine system (n = 35) or endometrial resection (n = 45). Blood loss assessment charts were used to measure menstrual blood loss. Results: Total bleeding score/month decreased from a baseline median of 47.26 to 33.5 (P<0.01) for the levonorgestrel intrauterine system and from 47.13 to 33.9 (P<0.01) for transcervical resection of the endometrium. There was no statically difference in bleeding score before and during treatment between the two groups of women. Conclusion: Both treatments levonorgestrel intrauterine system and transcervical resection of the endometrium efficiently reduced menstrual bleeding. levonorgestrel intrauterine system should be considered the first-line treatment for idiopathic menorrhagia because it is easy to insert, has a sustained effect, provides contraception, may reduce the need for surgery, and is cost-effective and well tolerated.

Do adjunctive antimicrobials improve the outcome of non-surgical peri-implantitis treatment?

Design This study was a single-centre, single-blind, controlled parallel group randomised control trial.Case selection Participants included those referred to The Hague Clinic for Periodontology in the Netherlands. The selection criteria included patients diagnosed with peri-implantitis, defined as marginal bone loss of >2 mm in addition to bleeding or suppuration on probing and a probing depth of >5 mm. The study was carried out over seven years and involved a control group (full mouth non-surgical peri-implantitis treatment) and a test group (non-surgical peri-implantitis treatment combined with systemic antimicrobials). Data analysis Sixty patients were recruited (30 allocated to each group) and 57 completed follow-up and were analysed according to the intention to treat principle. The patients were reviewed monthly and clinical data according to the parameters being measured were recorded. Microbiological analysis was also carried out. The power calculation was based upon the primary outcome measure of interest: bleeding on probing (BoP).Results The primary outcome parameter being measured was change in full mouth BoP and this study concluded that there were no significant differences in bleeding scores between the control and intervention at three months post-treatment. Secondary outcome parameters being measured included full mouth peri-implant and periodontal plaque scores (PS, %), clinical attachment levels, suppuration scores (SS, %), mean probing depths, mean peri-implant bone levels, change in detection frequency of periodontal pathogen species over the study duration, adverse event occurrence and need for additional surgical treatment. No significant differences were noted between the two groups for any clinical parameter.Conclusions Antimicrobial therapy does not lead to improved patient outcomes in terms of reducing microbial load and reducing pocket depth. Based on this study, there is inadequate evidence to support the use of adjunctive antimicrobials for the non-surgical treatment of peri-implantitis.

Practice Patterns for Diagnosis of Type 1 Von Willebrand Disease and Effect of Age on Von Willebrand Factor Levels: A Single Institutional Retrospective Study

IntroductionType 1 von Willebrand disease (VWD 1) accounts for ~75% of VWD. The National Heart, Lung, and Blood (NHLBI) VWD guidelines recommend VWF:Ag and VWF:RCo cut-off levels of <30 (IU/dL or %) for definite laboratory diagnosis of VWD 1. However, guidelines indicate that patients with “low VWF” (VWF:Ag and VWF:RCo in the 30-50 IU/dl range) could be candidates for agents to increase VWF levels if they are at risk for bleeding. Here we examine the diagnostic practices for VWD at Mayo Clinic Rochester by determining the proportion of patient currently classified as VWD 1 that meet NHLBI criteria for “low VWF”. In addition, we assess changes in the laboratory phenotype of the aging population of patients with “low VWF” and VWD 1.MethodsPatients with a diagnosis of VWD 1 at our institution were identified through our institutional hemophilia treatment center database (1986 to 2017). All available VWF:Ag and VWF activity (ristocetin cofactor assay [VWF:RCo] and latex immuno-activity assay [VWF:Ab]) levels performed at our institution and available in our electronic medical record (EMR) were recorded. Exclusion criteria included confounding variables known to effect VWF levels (eg,. hormonal therapy, pregnancy, desmopressin, or VWF/VIII concentrate administration) at the time of first laboratory assessment (VWF:Ag and VWF activity (by either VWF:Ab or VWF: RCo) at our institution. Bleeding score, retrospectively assessed using the MCMDM-1 VWD bleeding assessment tool (BAT), at the time of first clinical evaluation was recorded if enough information was available in the EMR. All VWF testing was recorded for comparative analysis between the first and the most recent measurements within the study period. Patients were not included in age-related analysis if the most recent laboratory values were obtained in the presence of the confounding variables noted above. Statistical analysis was performed using JMPfor paired t-tests and STATA for multilevel mixed-effects regression analysis.Results78 patients (50 F) met study criteria. Median age at initial presentation at our institution was 27.5 (0-75) years. Medians (ranges) for VWF:Ag (n=78), VWF:Ab (n=41), and VWF:RCo (n=75) were 39 (5-60)%, 37 (19-53)%, and 36 (11-62)%, respectively (reference ranges 55-200% for VWF and factor VIII values). Coagulation factor VIII activity (FVIII:C) was 63 (10-122)% (n=78). Of 37 patient with available blood type results, 23 (62%) were blood group O. 56% of patients (n=44) met NHLBI criteria for classification as “low VWF” (Figure 1, Panel A). There was no difference in bleeding score between patients with VWD 1 (median bleeding score: 4 (0-14), n=22) compared to those with “low VWF” (median bleeding score: 4 (0-14), n=37).54 patients had repeat laboratory testing at 4.5 (0-29) years after initial testing. VWF antigen and activity levels were compared in those who had repeat testing done >1 year (n=36) after initial lab testing at our institution. Median age of patients at time of most recent measurement was 42.5 (5-87) years compared to 35.5 (0-75) years at first measurement. VWF:Ag was significantly higher in the most recent measurement compared to the first measurement (p< 0.05, Figure 1, Panel B ). There was no statistically significant difference between VWF activity levels in the first versus the most recent measurement.There was a non-significant trend towards increasing VWF:Ag with increasing age; however when stratified into “low VWF” and VWD 1 disease groups, there was a significant relationship between VWF Ag and age in the “low VWF” group with mixed effects regression model (coefficient: 0.207, p:0.043).ConclusionApproximately 55% of patients with a clinical diagnosis for VWD 1 meet criteria for “low VWF.” In our cohort, there was no difference in bleeding (BAT) scores between the two groups; however our analysis is limited by its retrospective nature. We also demonstrate a statistically significant increase in VWF:Ag with aging; however, with regression analysis, this change was only noted in those in the “low VWF” group. Larger prospective studies controlling for confounding factors are needed to further demonstrate the effect of age on VWF antigen and activity levels. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prospective Diagnosis of VWD in a Large Cohort of Patients with Bleeding Symptoms through the Zimmerman Program

Prospective Diagnosis of VWD in a Large Cohort of Patients with Bleeding Symptoms through the Zimmerman Program

Bleeding score in type 1 von Willebrand disease patients using the condensed MCMDM-1 vWD validated questionnaire.

Assessment of the severity of bleeding symptom has led to the evolution of bleeding assessment tools which are now validated. To administer the condensed molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease VWD (MCMDM-1 vWD) questionnaire to the Omani type 1 vWD patients and correlate it with the laboratory parameters. Patients and controls were personally interviewed and the condensed MCMDM-1 vWD questionnaire administered by a single investigator. Bleeding score (BS) was calculated, based on the presence or absence of the bleeding symptoms according to a standard validated questionnaire in both the patients and the controls. The median age of the patient cohort was 27 (range, 7-49) years with 60.87% of females. The median time to administer condensed MCMDM-1 BS questionnaire was 11minutes (interquartile range-IQR;7,16). Overall, bleeding from the oral cavity was the most predominant symptom (63%). The median BS was 5 (IQR;1,8) although individual scores ranged between 0 and 29. However, there was no statistically significant difference in BS between genders (males: median 4; IQR 1,6 and females: median 5, IQR 1,10) (P>.05, Kruskal-Wallis test) The Spearman's correlation value of BS was weak with FVIII:C levels and von Willebrand Ristocetin co-factor activity; very weak with von Willebrand Antigen level, and moderate with vonWillebrand Collagen Binding activity being -0.29, -0.28, -0.14 and -0.43, respectively. The BS reflects the severity of bleeding among the vWD patients. Although the BS was abnormal, it did not correlate significantly with the surrogate laboratory parameters [P>.05].

Evaluation of a Standardized Approach to the Diagnosis of Mild Platelet Function Defects: Recommendation for a Targeted Approach to the Diagnosis of Mild Platelet Function Defects and Identification of a Subset of Children with a "Developmental" Form

Mild platelet function defects (MPFD) are a variable group of common inherited disorders characterized by mucocutaneous bleeding and excessive bleeding with trauma, surgery and procedures. The diagnosis is often based on subjective interpretations of expensive platelet function tests that require a substantial volume of blood. Furthermore, the diagnosis of MPFD can significantly limit participation in contact sports and physically demanding careers. To explore these issues, a retrospective chart review of patients from the Comprehensive Center for Bleeding Disorders of the BloodCenter of Wisconsin with a diagnosis of MPFD, and who had at least one follow-up evaluation was undertaken. The majority of patients had been evaluated by a two-step process; initially screened with CBC, PT, PTT, TT and a von Willebrand factor (VWF) panel. If these tests were normal, platelet function was assessed with light transmission aggregometry and chemiluminesence detection of ATP release in platelet rich plasma by the agonists TRAP, arachidonic acid (0.5 nM), ADP (10 uM), collagen (2.5 ug/mL) and high and low dose ristocetin.One hundred forty-eight patients diagnosed with a primary MPFD between 1982-2014 and with at least one recorded follow-up were identified. Bleeding scores were assigned by a system incorporating principles developed for the ISTH bleeding assessment tool. Patients ranged in age from 2 months to 57 years. For assessment of age on platelet function, patients were grouped as follows: Group A <2 years (N=23), Group B 2-4 years (N=33), Group C 5-8 years (N=36), Group D 9-16 years (N=30), and group E >16 years (N=26).At diagnosis, median bleeding score was 3 (range 0-12). Bleeding scores increased with age (p<.0001); the median (range) score was 2 (0-8) for A, 2 (0-5) for B, 3 (0-9) for C, 3 (0-7) for D and 4 (0-12) for E. There was no difference in gender by age group except group E with 23 females and 1 male; twenty of the 23 females reported menorrhagia. One hundred twenty eight (86%) of the patients had abnormal ATP release (122) or platelet aggregation (6) in the presence of ADP, the most common defect identified. Of those with abnormal release of ATP, 50% had another platelet function abnormality; there was no difference in bleeding scores between those with either single or multiple abnormalities. Of those who did not have abnormal aggregation or release with ADP, 8 had an abnormal response(s) with collagen alone and 1 had abnormal ATP release with arachidonic acid alone. At the most recent follow-up visit, (median 97 months, range 1-368 ) after the initial evaluation, the interim median bleeding scores were lower; for each age group the bleeding score (range) was 2 (0-8) for A, 1 (0-6) for B, 3 (0-7) for C, 2 (0-8) for D and 3.5 (0-10) for E. When compared to the oldest group (E), groups B and D showed a statistically significant difference (p <0.05).Twenty-nine of the patients had follow-up platelet function studies; of these, 13 (all were children) had a significant decrease in bleeding score and normalization of platelet function studies. There were no differences in age, gender, or family history of bleeding between those with persistent MPFD and those with normal follow-up platelet function tests. The persistent group had higher initial (p<0.03) and follow-up (p<0.02) bleeding scores. Those with normalization had a significant decrease in bleeding scores from diagnosis to follow-up (p<0.01) while the persistent MPFD group had no difference.These results suggest that a more targeted approach utilizing the analysis of ATP release by ADP, with TRAP release to confirm the presence of granules, will identify the majority of patients with mild platelet function defects. For those with suspected MPFD and normal ATP release with ADP, a full panel of agonists followed by additional step-wise evaluation as recommended by the ISTH should be undertaken. Limiting initial platelet function testing will reduce the volume of blood required and the cost. The reassessment of platelet function studies in patients with MPFD whose bleeding symptoms subside will identify a subset of these patients with normalization of platelet function. This group will no longer require treatment for procedures and restrictions of career choices or athletic pursuits. Thus, by utilizing a standard approach, patients with MPFD can be diagnosed and managed more efficiently and effectively with less cost to both the patient and healthcare system. DisclosuresFriedman:Alexion: Speakers Bureau; Novo Nordisk: Consultancy; CSL-Behring: Consultancy; Instrumentation Laboratories: Consultancy. Flood:Baxter: Consultancy; CSL Behring: Consultancy. Jobe:Bayer: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Gill:Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees.

Safety and efficacy of pre-incisional peritonsillar lornoxicam in paediatric post-tonsillectomy pain: a prospective double-blind, placebo-controlled, split-body clinical study.

To evaluate the risk of peri-operative bleeding and re-intervention with peritonsillar lornoxicam infiltration in paediatric tonsillectomy. Prospective, randomised, double-blinded, placebo-controlled, split-body study. University hospital. A total of 68 patients (7-15 years), ASA I-II, scheduled for tonsillectomy divided into two groups (n = 34) to receive bilateral peritonsillar saline infiltration (placebo group) or peritonsillar saline infiltration in one tonsil (placebo side) and 8 mg lornoxicam in the other tonsil (intervention side; study group). Drugs were administered after induction of anaesthesia and before start of surgery. Intra-operative and postoperative bleeding score, platelet aggregometry before and 30 min after study drug administration, the verbal rating pain scale, time to first postoperative analgesic request, total analgesic consumption during 1st 24 h postoperative and adverse effects were evaluated. The difference in bleeding score between groups did not reach our definition of statistical significance (P < 0.05). Platelet aggregometry tests did not change significantly with time between groups. Lower postoperative pain scores, longer time to first analgesic request (372.76 ± 82.15 versus 64.89 ± 25.76 min P < 0.001) and lower paracetamol consumption (421.76 ± 125.63 versus 690.29 ± 141.47 mg, P < 0.001) were recorded in study group compared with control group. No patient required hospital re-admission or re-operation because of postoperative tonsillar bed bleeding. The lack of significant complications suggests that pre-incisional peritonsillar lornoxicam followed by intravenous paracetamol rescue analgesia may be safe for tonsillectomy in children. To avoid conflict with intra-operative bleeding, postoperative infiltration of lornoxicam is recommended.

The Management of Bleeding Risk in Von Willebrand Disease: Should Blood Group O Make a Difference?

▪Type 1 von Willebrand disease (VWD) is a common inherited bleeding disorder characterized by a quantitative deficiency of von Willebrand factor (VWF) and excessive mucocutaneous bleeding. It is well known that von Willebrand factor (VWF) levels are significantly lower in persons with ABO blood group O and that there is a significantly higher prevalence of blood group O in patients with a diagnosis of type 1 VWD. This raises a question important to the clinical care of patients with low VWF; is there a difference in bleeding risk in patients with a deficiency of VWF on the basis of blood group O versus those with a deficiency of VWF due to a sequence variation in the VWF gene. To explore this question, we examined index cases enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD with a quantitative deficiency of VWF including those with a phenotypic diagnosis of low VWF [von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor activity (VWF:RCo)≤ 50 U/dL and >40 U/dL], type 1 VWD (VWF:Ag or VWF:RCo≤40 U/dL) and type 1C VWD (VWF:Ag ≤30 U/dL and VWF propeptide/Ag ratio >3 indicating increased clearance of VWF). VWF:Ag, VWF:RCo, VWF propeptide and multimer distribution were analyzed in the clinical hemostasis laboratory at the BloodCenter of Wisconsin. Full length VWF gene sequencing including intron-exon boundaries was performed for all index cases. Bleeding symptoms were scored utilizing the ISTH, MCMDM1 and PBQ bleeding assessment tools. Since there was a high correlation among bleeding scores with these three methods, the ISTH score was utilized for this analysis.Complete data were available for 91 subjects with low VWF, 161 subjects with type 1 VWD, 53 subjects with type 1C VWD and 74 normal control subjects. Median ages were not different among the diagnostic groups. As expected based on previous reports, the groups of VWD patients with lower VWF:Ag values (Mean±1SD) had an increased percentage of subjects with an identified sequence variation; low VWF group, VWF:Ag 50.4±8.4, 38% with sequence variation; Type 1 VWD, VWF:Ag 30.8±11.6, 70% with sequence variation; and Type 1C VWD, VWF:Ag 9.8±5.9, 83% with sequence variation. The low VWF group and the type 1 VWD groups both had a significantly increased frequency of subjects with blood group O (70 – 80%) vs. nonO (19-30%) in comparison to those with type 1C in whom the frequency of blood group O (57% ) vs. nonO (43%) was not different than that in the normal control population (43% O vs. 57% nonO). This suggests that the type 1 and low VWF groups have a significant proportion of subjects with low VWF on the basis of blood group O alone. Since those subjects with a diagnosis of low VWF or Type 1 VWD who have no identifiable sequence variation are more likely to be affected by blood group O alone, we examined the ISTH bleeding scores in subjects with similar VWF levels and blood group O with and without an identifiable VWF gene sequence variation. We found that there was no difference in the ISTH bleeding scores in blood group O subjects regardless of the presence of a VWF gene sequence variation; low VWF, no sequence change (N=45), median bleeding score 6.0 vs. 5.0 with sequence change (N=27); type 1 VWD, no sequence change (N=39), median bleeding score 5.0 vs. 5.0 with sequence change (N=73); type 1C VWD, no sequence change (N=6), median bleeding score 7.0 vs. 7.0 with sequence change (N=24). There were no differences in median bleeding scores in blood group O vs. nonO groups, and none in the nonO groups with or without sequence variation in any of the VWD phenotypic diagnostic categories. There were no significant differences in bleeding scores by gender in any of the diagnostic categories.In conclusion, we found no differences in ISTH bleeding scores in the groups of subjects most likely to have low VWF on the basis of blood group O alone, i.e., those with blood group O and no identifiable VWF gene sequence variation compared to those with VWF gene sequence variations. Thus, management of persons with VWF deficiency should be based on baseline VWF levels and not modified in those with blood group O. DisclosuresNo relevant conflicts of interest to declare.

Impact of Age and Gender on Bleeding Score in Type 1 VWD Using the ISTH-BAT

▪The ISTH Bleeding Assessment Tool (ISTH-BAT) was introduced in 2010 to improve on the earlier BATs and in particular to have greater accuracy in the pediatric and female population by including additional questions for neonatal bleeding and menorrhagia. The recently published cut off for positive or abnormal bleeding score (BS) is ≥ 4 in adult males, ≥ 6 in adult females and ≥ 3 in children. Here we examine the use of the ISTH-BAT in type 1 VWD and its ability to better characterize bleeding in females and children as well as the impact of menorrhagia on bleeding scores in females during aging.We analyzed 323 Index Cases (IC) and 482 Affected Family Members (AFM) enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCB-VWD) with a phenotypic diagnosis of type 1 (including type 1, type 1C, type 1-severe, and low VWF). Bleeding symptoms were quantified using three different scoring systems (MCMDM-1, PBQ and ISTH-BAT), however the BS results in this analysis focus on the ISTH-BAT. Subjects were categorized by the following age groups: infant (0-2), child (3-12), adolescent (13-17), young adult (18-35), middle age (36-55), older adult (>55).Mean BS were slightly higher in both infant and child-aged males (4.5 and 4.6) compared to females (1.8 and 4.4), but the difference is not significant (p= 0.2828 and 0.5455). Higher bleeding scores in infant males were due in part to neonatal bleeding score from circumcision (13.6% of neonatal cases). The most reported bleeding symptoms in infant and child-aged males were cutaneous bleeding (61.0%), epistaxis (52.5%) and oral bleeding (25.4%). Females of this age group also presented with similar symptoms of cutaneous bleeding (64.4%), epistaxis (54.2%) and oral bleeding (30.5%).Surprisingly, there was no significant difference in total BS between adolescent males and females (mean 5.0 and 5.65, p= 0.4607). The frequency of reported bleeding symptoms in adolescent males was due to epistaxis (69.6%), cutaneous bleeding (43.5%), and minor wound bleeding (39.1%), while adolescent females reported menorrhagia (80.3%), cutaneous bleeding (65.6%), minor wound bleeding (64.4%) and epistaxis (32.8%).Bleeding symptoms reported by adults (≥18) varied by gender with males most often reporting cutaneous bleeding (50.0%), epistaxis (42.9%), oral bleeding (42.9%) and surgery (39.3%), whereas females suffered from menorrhagia (85.9%), cutaneous bleeding (80.4%), epistaxis (42.4%), minor wound bleeding (38.0%), and bleeding following tooth extractions (34.8%).Female IC (n=212) and AFM (n=280) both showed a gradual increase of BS over time (2.8 and 1.2 points per decade) whereas the BS is relatively flat over time for male IC and AFM. Analysis of female unaffected family members (n=759) showed a similar increase of BS with age (1 point per decade). To show the contribution of female specific bleeding to the overall score, we calculated a modified BS removing the menorrhagia and postpartum subscores. Interestingly, the modified BS also increased over time suggesting that other bleeding symptoms contribute to female bleeding as they age.In summary, we have shown the utility of the ISTH-BAT to characterize the bleeding in our type 1 VWD, particularly in infants and females. Infant and child-aged subjects with type 1 VWD do not show any significant difference in BS between males and females and they report similar bleeding symptoms of cutaneous bleeding, epistaxis and oral bleeding. While adolescent males and females have similar total BS, their type of bleeding symptoms vary. The BS in adult females continues to increase with age, however menorrhagia and postpartum bleeding are not the only the contributors, suggesting that there are other bleeding symptoms that account for the gradual increase of BS in females over time. DisclosuresFriedman:Alexion: Speakers Bureau; Octapharma: Consultancy; Biogen Idec: Consultancy; CSL Behring: Consultancy.

Critical Importance Of VWF Propeptide (VWFpp) In The Diagnosis Of Type 1 Von Willebrand Disease (VWD)

Type 1 VWD is the most common form of VWD and is characterized by quantitative deficiency of VWF. Mechanisms causing type 1 VWD include decreased VWF synthesis due to promoter polymorphisms, decreased VWF secretion with intracellular retention/degradation, and increased clearance of VWF from plasma (type 1C VWD). VWF and its propeptide (VWFpp) are released into plasma in equimolar amounts but have very different half-lives (8 – 12 hours and 2-3 hours, respectively). The assay of VWFpp can be used to assess VWF synthesis, secretion, and clearance. Reduced VWFpp level indicates reduced VWF synthesis or secretion. An increased VWFpp/VWF:Ag ratio is expected when VWF is cleared rapidly from plasma (type 1C VWD), while decreased VWF secretion/intracellular retention results in a normal ratio. We enrolled 502 type 1 VWD index cases with a pre-existing diagnosis of type 1 VWD through the Zimmerman Program for the Molecular and Clinical Biology of VWD. We confirmed 262 index cases as type 1 VWD (VWF:Ag or VWF:RCo ≤ 40 IU/dL). Of the confirmed type 1 VWD cases, 58 met the criteria for type 1C VWD with VWFpp/VWF:Ag ≥ 3 and VWF:Ag ≤ 30 IU/dL, and 12 met the criteria for “Type 1 – Severe” with VWF:Ag of 1 – 5 IU/dL and VWFpp/VWF:Ag < 3. Type 1C VWD comprised 22% of all type 1 VWD cases. The type 1C cohort included several individuals previously diagnosed as type 2A (11), type 2M (2), and “Unclassified” (3). The most significant reclassification involved 7 cases previously diagnosed as type 3 VWD – these patient had detectable VWF:Ag (2 – 6 IU/dL) and VWFpp (14 – 66 IU/dL), and elevated VWFpp/VWF:Ag (4.2 – 33.0). Although plasma VWF:Ag is very low in these patients, they might be expected to have normal platelet stores of VWF:Ag, unlike type 3 VWD patients. Type 3 VWD patients in our study had undetectable (<1 IU/dL) VWFpp and VWF:Ag. In fact, type 1C VWD comprised the majority of severe type 1 VWD cases. At very low VWF:Ag levels (2 – 10 IU/dL), 76% of index cases had a type 1C phenotype, while the remainder had normal VWFpp/VWF:Ag consistent with a decreased secretion phenotype. In the VWF:Ag of 11 – 20 IU/dL group, 38% were type 1C. At still higher VWF:Ag levels (21 – 30 IU/dL), only 7% had a type 1C phenotype and the majority had a decreased secretion phenotype. Additionally, 43% of the type 1C cohort had VWFpp levels below the normal range, indicating reduced synthesis/secretion is also involved in the mechanism causing type 1C VWD. Mutations associated with type 1C were located in the VWF D3, A1, and D4 domains while decreased secretion variants were located primarily in the D1, D2, and D3 domains. Somewhat surprisingly, no difference in bleeding score was identified between type 1C and other type 1 patients. We can conclude that a reduced VWF survival phenotype (type 1C) is very frequent in severe type 1 VWD patients with VWF:Ag < 20 IU/dL. Identification of type 1C VWD is important because the rapid clearance of VWF in these patients may preclude the use of desmopressin, which is commonly given in type 1 VWD, but may be insufficient to achieve hemostasis in type 1C patients. Disclosures:No relevant conflicts of interest to declare.

Bleeding Scores in Von Willebrand Disease (VWD) Re-Visited: Analysis of the TS Zimmerman Program for the Molecular and Clinical Biology of VWD

Quantitation of bleeding severity in VWD has recently been investigated utilizing a standardized bleeding score developed through a European study (MCMDM-1) of a large cohort of VWD type 1 families but has not been evaluated in other types of VWD. We analyzed data from the TS Zimmerman Program for the Molecular and Clinical Biology of VWD in order to determine the relative impact of various VWD molecular variants on the clinical bleeding phenotype of individuals with VWF abnormalities. After obtaining informed consent, demographic data and bleeding histories were obtained from subjects through administration of a standardized questionnaire by trained personnel; bleeding score (BS) was calculated by the method of the MCMDM-1. VWF assays were performed in the central laboratory, including quantitation of VWF by VWF:Ag; functional analysis by ristocetin cofactor (VWF:RCo) and collagen binding (VWF:CB); multimer analysis; and DNA sequencing of the VWF gene including coding sequences, intron-exon boundaries and promoter regions. A total of 212 Index Cases (IC) including 149 with type 1 VWD, 17 type 2A, 8 2B, 4 2M, 6 2N and 28 type 3), 346 affected family members and 417 unaffected family members of the IC were identified by their primary hematologist and compared to 234 Normal Control subjects (NC). Subjects with VWD ranged in age from 1–76 years, median 17; NC ages ranged from 2–74 years, median 40. Male to female ratios were similar in type 1 VWD (0.44) and NC (0.34) but equivalent in type 2 (0.94) and type 3 VWD (0.87). Subjects with each type of VWD had significantly higher BS (median, 25–75% interquartile range) than NC (p<0.001); type 1 IC (6, 3–10); type 2 IC (7, 3–13); type 3 IC (15, 10.5–23); and NC (0, −1–1). Age was significantly correlated with BS in type 1 IC (p<0.0001). Males vs. females within each group did not have significantly different BS, nor did those with blood group O vs. non-O; there were significant differences in comparisons of BS in IC vs. NC (p<.001) in each of these subgroups. BS (median, 25–75% interquartile range) in families differed between the IC (6, 3–10), affected family members (1, −1–4), unaffected family members (0, −1–2) and NC (0, −1–1). VWF DNA sequencing revealed known mutations or new SNPs in 21/57 (37%) type 1 IC and 17/48 (35%) NC. In contrast to results from the MCMDM-1, there was no difference in BS in those with or without a DNA sequence variation within the type 1 IC group. In addition, there were no differences in BS within the NC group in the presence or absence of a sequence variation but significant BS differences were found in IC compared with NC (p<.001) regardless of the presence of a DNA sequence variation. Comparisons of BS (mean ± SD) in IC with type 1 VWD and VWF:Ag< 30 (N=20) compared to IC with type 2 VWD and VWF:Ag<30 (N=31) revealed higher BS in type 2 IC (8.5 ± 6.3) than type 1 IC (6.9 ± 5); p<0.05). This study of the quantitation of bleeding severity in subjects with both quantitative defects in VWD (type 1 and 3) and qualitative defects (type 2) revealed that the BS is significantly higher compared with NC in those with type 2 and 3 VWD as well as has been previously shown in type 1 VWD. The presence of a DNA sequence variation was not associated with higher bleeding scores in type1 VWD. A comparison of BS in type 1 IC vs. type 2 IC with similar concentrations of VWF in plasma (VWF:Ag), suggests that the molecular abnormalities present in type 2 subjects results in a more severe bleeding phenotype in spite of the same concentration of antigen. The strong correlation of age with bleeding score warrants additional investigation of bleeding history instruments to identify pediatric patients at risk. We conclude that improved understanding of the clinical consequences of VWF defects will be enhanced by investigation of their impact on clinical bleeding phenotypes in well characterized patients with VWD.

Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease.

Given the challenges involved in obtaining accurate bleeding histories, attempts at standardization have occurred and the value of quantifying hemorrhagic symptoms has been recognized. An extensive validated bleeding questionnaire (MCMDM-1VWD) was condensed by eliminating all details that did not directly affect the bleeding score (BS) and the correlation between the two versions was tested. Additionally, the diagnostic utility of the condensed version was prospectively tested. Data on 259 individuals who were administered the questionnaire are presented here; 217 being prospectively investigated for von Willebrand disease (VWD) (group 1) and 42 previously known to have type 1, 2 or 3 VWD (group 2). Of the 217 prospectively investigated, 35 had positive BS (> or =4) and 182 had negative scores. Seven individuals (all with positive BS) had laboratory results consistent with type 1 VWD. This results in a sensitivity of 100% and a specificity of 87%. The positive predictive value is 0.20 and the negative predictive value is 1. The correlation between the full MCMDM-1VWD and condensed versions is excellent (Spearman's 0.97, P < 0.001, linear regression r(2) = 96.4). Inter-observer reliability for the condensed version is reasonable (Spearman's 0.72, P < 0.001 and intra-class correlation coefficient 0.805, P < 0.001). There was a significant difference in BS between subtypes of VWD, with type 3 >> type 2 >> type 1 VWD (anova P < 0.001). There is a strong inverse relationship between VWF:Ag level and BS (Spearman's -0.411, P < 0.001). The Condensed MCMDM-1VWD Bleeding Questionnaire is an efficient, effective tool in the evaluation of patients for VWD.

Treatment of menorrhagia with a novel 'frameless' intrauterine levonorgestrel-releasing drug delivery system: a pilot study

Objective To evaluate the effect on menstrual blood loss of a novel 'frameless' intrauterine drug delivery system, the FibroPlant™ levonorgestrel intrauterine system (IUS), releasing 14 μg of levonorgestrel/day. An ancillary objective was to evaluate the contraceptive performance. Study design This was an open-label, non-comparative ongoing pilot study. Thirty-two insertions were performed in fertile women aged between 31 and 51 years for the treatment of menorrhagia, as well as for contraceptive purposes. Fifteen women who developed excessive bleeding were fitted with the FibroPlant levonorgestrel IUS immediately following the removal of a copper-bearing intrauterine device (IUD), the GyneFix® IUD. To discriminate between menorrhagia and normal menstrual blood loss, women were evaluated using a simple visual assessment technique. The trial covered a period from a minimum of 1 month up to 23 months. Results At the time of study analysis, the total number of woman-months was 361. Fourteen of the women had had the FibroPlant levonorgestrel IUS in place for more than 1 year, and 29 women for 6 months or more. All women reported greatly reduced bleeding. However, no cases of amenorrhea resulting from endometrial suppression were encountered. The reduction of bleeding was substantial after 1 month of treatment and decreased further over the next months to remain stable thereafter. The mean bleeding score before treatment was 338 (range 185–740) in the group who had had no prior use of an IUD and 368 (range 185–890) in the group with prior IUD use. The mean bleeding score dropped to a mean score of 70 (range 5–210) in the 'no prior IUD use' group and to a mean score of 52 (range 3–150) in the 'prior IUD use' group, after 1–23 months of follow-up. This result is highly statistically significant (p < 0.001). There were no statistical differences in bleeding scores before and during treatment between the two groups of women, with or without prior use of the copper IUD. Significant spotting was rare after the first 3 months following insertion. No complications (e.g. infection, expulsion or perforation) or pregnancies occurred. The FibroPlant levonorgestrel IUS was well tolerated by all women involved in the study and no systemic hormonal side-effects were reported. Conclusion The FibroPlant levonorgestrel IUS is effective in significantly reducing the amount of menstrual blood loss in women with menorrhagia. Strong endometrial suppression is the principal mechanism explaining both the effect on menstrual blood loss and the contraceptive performance of the IUS. There were no differences in bleeding scores before and during treatment between the two groups of women with or without prior use of the copper IUD, suggesting that the development of heavy bleeding was not related to the use of the IUD. The therapeutic effect of this contraceptive method is highly desirable, particularly in women with heavy bleeding or anemia in developing countries, as other treatment modalities are less effective, more costly, more invasive or inaccessible. The low daily release rate of levonorgestrel from the FibroPlant levonorgestrel IUS results in a low incidence of hormonal side-effects and reduces the likelihood of amenorrhea. The simple design characteristics and revolutionary anchoring system minimize the occurrence of complaints of pain and the incidence of expulsion.

Treatment of menorrhagia with a novel 'frameless' intrauterine levonorgestrel-releasing drug delivery system: a pilot study

Objective To evaluate the effect on menstrual blood loss of a novel 'frameless' intrauterine drug delivery system, the FibroPlant™ levonorgestrel intrauterine system (IUS), releasing14 μg of levonorgestrel/day. An ancillary objective was to evaluate the contraceptive performance.Study design This was an open-label, non-comparative ongoing pilot study. Thirty-two insertionswere performed in fertile women aged between 31 and 51 years for the treatment of menorrhagia, as well as for contraceptive purposes. Fifteen women who developed excessive bleeding were fitted with theFibroPlant levonorgestrel IUS immediately following the removal of a copper-bearing intrauterine device (IUD), the GyneFix® IUD. To discriminate between menorrhagia and normal menstrual bloodloss, women were evaluated using a simple visual assessment technique. The trial covered a period from a minimum of 1 month up to 23 months.Results At the time of study analysis, the total numberof woman-months was 361. Fourteen of the women had had the FibroPlant levonorgestrel IUS in place for more than 1 year, and 29 women for 6 months or more. All women reported greatly reduced bleeding. However,no cases of amenorrhea resulting from endometrial suppression were encountered. The reduction of bleeding was substantial after 1 month of treatment and decreased further over the next months to remainstable thereafter. The mean bleeding score before treatment was 338 (range 185–740) in the group who had had no prior use of an IUD and 368 (range 185–890) in the group with prior IUD use. Themean bleeding score dropped to a mean score of 70 (range 5–210) in the 'no prior IUD use' group and to a mean score of 52 (range 3–150) in the 'prior IUD use' group, after 1–23 monthsof follow-up. This result is highly statistically significant (p < 0.001). There were no statistical differences in bleeding scores before and during treatment between the two groups of women,with or without prior use of the copper IUD.Significant spotting was rare after the first 3 months following insertion. No complications (e.g. infection, expulsion or perforation) or pregnancies occurred.The FibroPlant levonorgestrel IUS was well tolerated by all women involved in the study and no systemic hormonal side-effects were reported.Conclusion The FibroPlant levonorgestrel IUS is effectivein significantly reducing the amount of menstrual blood loss in women with menorrhagia. Strong endometrial suppression is the principal mechanism explaining both the effect on menstrual blood loss and thecontraceptive performance of the IUS. There were no differences in bleeding scores before and during treatment between the two groups of women with or without prior use of the copper IUD, suggesting thatthe development of heavy bleeding was not related to the use of the IUD.The therapeutic effect of this contraceptive method is highly desirable, particularly in women with heavy bleeding or anemiain developing countries, as other treatment modalities are less effective, more costly, more invasive or inaccessible. The low daily release rate of levonorgestrel from the FibroPlant levonorgestrel IUSresults in a low incidence of hormonal side-effects and reduces the likelihood of amenorrhea. The simple design characteristics and revolutionary anchoring system minimize the occurrence of complaints ofpain and the incidence of expulsion.