Haemostasis Bleeding Assessment Tool Research Articles

Enhanced thrombin and plasmin generation profiles in alpha-2-antiplasmin–deficient patients: Data from the Rare Bleeding disorders in the Netherlands study

Backgroundα2-Antiplasmin (A2AP) deficiency is a rare and often unidentified disorder characterized by increased fibrinolysis and subsequent bleeding. Global hemostasis assays may increase insight into the altered coagulation and fibrinolysis in these patients. ObjectivesTo explore thrombin and plasmin generation profiles in A2AP-deficient patients, corresponding A2AP activity levels and associated bleeding phenotypes. MethodsThe Nijmegen hemostasis assay was used to assess thrombin and plasmin generation in 23 A2AP-deficient patients (median age, 50 years; 70% women) from the cross-sectional Rare Bleeding disorders in the Netherlands study. Analyzed parameters included thrombin peak height, thrombin potential, fibrin lysis time, plasmin peak height, plasmin velocity index, and plasmin potential. These parameters were expressed as percentages of a reference obtained from 37 healthy controls (median age, 46 years; 57% women). The Nijmegen hemostasis assay data were correlated with A2AP activity levels and International Society on Thrombosis and Hemostasis Bleeding Assessment Tool scores using Pearson correlation coefficients. ResultsPatients’ A2AP activity levels ranged from 23% to 83% (reference range, 89%-122%). Plasmin generation increased, as evidenced by significantly shorter fibrin lysis times (73%; P < .001) and higher plasmin peak heights (203%; P < .001), plasmin velocity indices (302%; P < .001) and plasmin potentials (154%; P < .001) in A2AP-deficient patients than those in healthy controls. Moreover, significantly higher thrombin potentials (146%; P < .001) and thrombin peak heights (132%; P < .001) were observed. Enhanced plasmin generation parameters showed statistically significant correlations with lower A2AP activity levels and higher International Society on Thrombosis and Hemostasis Bleeding Assessment Tool scores. ConclusionA2AP-deficient patients exhibited augmented plasmin generation profiles that correlated with A2AP activity level and bleeding phenotype. Interestingly, increased thrombin generation profiles were also found in these patients.

Platelet changes and bleeding symptoms in children, adolescents, and adults with 22q11.2 deletion syndrome.

The deletion region of 22q11.2 deletion syndrome (22q11.2DS) contains a gene encoding glycoprotein Ibβ (GPIbβ), which is required to express the GPIb/IX/V complex on the platelet surface. Therefore, patients with 22q11.2DS may have congenital platelet disorders. However, information is limited on platelets and bleeding symptoms. In this study, we investigated clinical information, including bleeding symptoms, platelet counts, and GPIb expression levels in children and adolescents/adults with 22q11.2DS. Thirty-two patients with 22q11.2DS were enrolled in a prospective cohort study between 2022 and 2023 at outpatient clinics within our institute. The median platelet counts in adolescents/adults with 22q11.2DS were significantly lower than those in children (p<.0001). A gradual decrease was found along with increasing age (p=.0006). Values of median GPIb expression on platelet surfaces (66% in children and 70% in adolescents/adults) were significantly lower than those in healthy controls (p<.0001 and p=.0002). Bleeding symptoms included surgery-related bleeding (52%), purpura (31%), and epistaxis (22%); most of them were minor. The median International Society on Thrombosis and Hemostasis bleeding assessment tool score was not significantly different between children and adolescents/adults (p=.2311). Although there was an age-related decrease in platelet count and a disease-related decrease in GPIb expression, no difference in bleeding symptoms was found between children and adolescents/adults. 22q11.2DS overall had minor bleeding symptoms in daily life, and the disease had little effect on spontaneous bleeding. However, some patients had major bleeding events; further accumulation of data on hemostasis during surgery and trauma is required.

Rare bleeding disorders in Egyptian females presented with heavy menstrual bleeding: single-center study

BackgroundHeavy menstrual bleeding is an important health problem in women of reproductive age and is also one of the most common symptoms in women with bleeding disorders. Data about the frequency of rare bleeding disorders are limited, and population-based studies are lacking, so we aimed to determine the frequency of rare bleeding disorders among women presented with heavy menstrual periods that cannot be attributed to obvious problems.MethodsComplete blood count and bleeding profiles include activated partial thromboplastin time, prothrombin time, factor VIII activity assay, ristocetin cofactor activity, von Willebrand antigen assay, platelet aggregation tests and other factor assays in 100 out of 300 females presented with unexplained heavy menstrual period, pictorial bleeding assessment chart (PBAC) > 100 as a screening tool for heavy menstrual periods, and or International Society of Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) > 6.ResultsA total of 300 women with heavy menstrual periods without an obvious explained cause were included in our study. Among them, we found 100 (30%) females with a mean PBAC of 234 ± 147 and mean ISTH-BAT of 9 ± 5 denoting HMB may be due to underlying bleeding disorders. Among them, the most common diagnosis was VWD in 30 (30%). Other disorders were as follows: 28 (28%) cases with clotting factor deficiencies, 24 (24%) cases were found to have platelet dysfunction, and in 18% of our studied cases, we did not find a clear cause of their bleeding disorders (unknown).ConclusionRare bleeding disorders are not uncommon and require comprehensive hemostatic evaluation as well as simple tools like PBAC and ISTH-BAT questionnaires for the identification of females presented with unexplained HMB.

Gynecological bleeding in women with congenital bleeding disorders: A comprehensive cohort from Iran

BackgroundGynecological bleeding including menorrhagia and postpartum hemorrhage (PPH) face women's quality of life constantly with difficulties, especially those suffering from inherited bleeding disorders. In this study, we aim to evaluate gynecological bleeding particularly menorrhagia among Iranian women patients with inherited bleeding disorders admitted to the Iranian Comprehensive Hemophilia Care Center (ICHCC). MethodsThis study was conducted on 156 females aged ≥ 12 diagnosed with an inherited bleeding disorder in ICHCC. Demographic and laboratory data were documented for all patients. Bleeding questionnaires (the International Society on Thrombosis and Hemostasis bleeding assessment tool (ISTH-BAT), Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease (MCMDM-1), and Pictorial blood loss assessment chart (PBAC)) were filled out for all patients. For comparing metric and categorical parameters, Mann-Whitney was performed. Spearman's rho test was used for analyzing correlation. ResultsThe mean age of patients was 33. Von Willebrand disease (VWD), Factor (F) VII deficiency and combined factor deficiency were the most diagnosed disorders. The median of ISTH-BAT, MCMDM-1, and PBAC was 7,7, and 517, respectively. Menorrhagia was the most common reason for diagnosis. Menorrhagia and PPH domain scores ≥ 2 were recorded in 82 and 34 patients, respectively, and PBAC scores > 100 were seen in 118 patients. Significant positive correlations were observed between bleeding scores and menorrhagia and PPH scores. No significant correlations were recorded for VWF: Ag and VWF: RCo with menorrhagia and PPH scores; however, significant correlations were seen for VWF: Ag and VWF: RCo with bleeding score questionnaires. ConclusionMenorrhagia is the most common problem in females affected by different types of inherited bleeding disorders, particularly VWD. Increased awareness among gynecologists and hematologists about bleeding disorders in cases with unexplained menorrhagia is an essential step for optimal management.

Platelets from Ehlers-Danlos Syndrome Patients Exhibit Reduced GPVI Levels and Impaired Integrin αIIbβ3 inside-out Signaling

Background: Patients with Ehlers-Danlos syndrome (EDS) have a high susceptibility to bleeding. Easy bruising is included as a criterion for the classification of multiple types of EDS. Although the association between EDS and the tendency to bleed has been acknowledged for a long time, a definitive understanding of the underlying mechanisms contributing to bleeding diathesis in EDS patients is still lacking. Objective: To characterize platelet function in a cohort of EDS patients and a murine EDS model. Methods: A cohort of 53 patients with hypermobile (49%), classical (26%), classical-like (21%), or vascular (4%) types of EDS and a group of 53 healthy control subjects matched by age and gender were included in the study in accordance with the University of Iowa Institutional Review Board-approved protocol. The International Society of Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT) was used to assess the bleeding tendency in study participants. Because a single mutation in hypermobile type is currently unknown, we used Col5a 1 +/− mice as a murine model of the classical type of EDS. The function of human and mouse platelets was evaluated using standardized agonist-induced in vitro assays. Results: The mean ISTH-BAT score was 0.1 in healthy controls and 9.2 in EDS patients ( P &amp;lt; 0.001). An abnormal ISTH-BAT score was observed in 33 out of 53 (62%) EDS patients and 0 of 53 healthy controls ( P &amp;lt; 0.001). Platelets from EDS patients exhibited reduced aggregation and αIIbβ3 activation (with normal αIIbβ3 surface exposure) in response to stimulation with collagen, collagen-related peptide, or thrombin receptor activator peptide-6, compared to healthy controls. Platelet secretion of dense and α-granules and surface phosphatidylserine exposure were comparable between EDS and healthy subjects. Evaluation of collagen receptors on the surface of resting platelets showed a mild deficiency of GPVI in EDS patients compared to healthy controls ( P &amp;lt; 0.001), while the integrin α2 levels were similar in both groups ( P = 0.152). Analysis of GPVI signaling revealed downregulation of Syk (Y525/526), PLCγ2 (Y1217), and talin (S425) phosphorylation in EDS patients ( P &amp;lt; 0.05 vs. healthy controls), suggesting a defect in collagen-induced integrin αIIbβ3 inside-out signaling. Consistent with our observations in EDS patients, Col5a1 +/− mice demonstrated a bleeding tendency characterized by prolonged tail-bleeding time ( P &amp;lt; 0.05 vs. wild-type control). Platelet function testing showed that Col5a 1 +/− mouse platelets recapitulated the abnormalities detected in human EDS platelets. Conclusions: Our data corroborate the observation that EDS patients exhibit a high risk of hemorrhagic complications.EDS platelets are characterized by reduced baseline GPVI expression that was associated with decreased agonist-induced platelet aggregation, αIIbβ3 activation, and impaired collagen-induced integrin αIIbβ3 inside-out signaling.

Clinical and Laboratory Presentation and Underlying Mechanism in Patients with Low VWF.

Low von Willebrand factor (VWF) refers to subjects with plasma levels of 30 to 50 IU/dL. The mechanism of low VWF is poorly understood. We chose to determine the clinical presentation, laboratory phenotype, and underlying mechanisms of low VWF. We included 250 patients characterized with low VWF. The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) was used to assess clinical symptoms. To determine the underlying mechanisms of low VWF, we used as markers the VWF propeptide (VWFpp) assay and FVIII:C/VWF:Ag ratio for VWF synthesis and the VWFpp/VWF:Ag ratio for VWF clearance. Results were compared with those of 120 healthy controls. Cases with abnormal screening tests were further evaluated for coagulation factor levels and platelet disorders. The median age of the cohort was 35 years (range 3-85), 21% were children (n = 53), 34% were adult males (n = 85), and 45% (n = 112) were adult females. According to the ISTH-BAT, abnormal bleeding was found in 35% of children, 47% of males, and 49% of females. No association was found between VWF activity levels and ISTH-BAT. Patients showed an overall decreased VWF synthesis/secretion and an enhanced VWF clearance was identified in 33% of them. In 89 patients (36%), there were other hemostasis-related defects, but there was no difference in the ISTH-BAT between the two groups. Our findings indicate that reduced VWF synthesis/secretion and enhanced VWF clearance are major mechanisms of low VWF levels. Patients with low VWF have significant bleeding manifestations. While other hemostasis defects occurred together with low VWF, this combination did not exacerbate clinical symptoms.

Platelet Electron Microscopy Does Not Correlate with Bleeding Scores in a Pediatric Population

Background:Platelet electron microscopy (PEM) is the diagnostic test for delta storage pool deficiency, a bleeding disorder due to qualitative or quantitative deficiency in dense granules leading to abnormal platelet function. Many people have non-syndromic forms which are challenging to diagnose. Aims: We aimed to describe the population for whom PEM is sent and correlate PEM results with bleeding phenotype and platelet function testing. Methods:We performed a single-center, retrospective study including patients who had PEM sent between 2/1/2018 and 8/30/2022 and had a hematology encounter. Demographics, PEM results, platelet aggregation studies, von Willebrand factor (VWF) testing, coagulation studies, genetic testing, and International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT) scores were collected. ISTH-BAT was calculated based on the note closest in time to PEM testing. ISTH-BAT was either retrospectively calculated from clinical documentation or extracted as calculated by the clinician during the visit. ISTH-BAT normal range was defined as &amp;lt;4 for adult males, &amp;lt;6 for adult females, and &amp;lt;3 for children (&amp;lt;18 years) (Elbatarny et al., Hemophilia 2014). Descriptive statistics were used to summarize the results. Pearson's correlation coefficient and a Student's t-test were used for normally distributed data and Spearman rank correlation for non-parametric data. Categorical variables were compared with a Pearson chi-squared test. Statistical analysis included the first PEM result. Alpha&amp;lt;0.05 was considered significant. Results: There were 92 PEM tests sent from 77 subjects (Table 1). PEM testing was completed at either University of Toledo (N=79, normal range: 4-6 dense granules per platelet [dg/pl]) or Mayo Clinic (N=13, normal range: ≥1.2 dg/pl). Forty-six (60%) subjects had abnormal PEM results. Repeat testing was sent from 15 subjects, 13 of whom had an initial abnormal reported result with 12/13 repeat tests confirmed abnormal. Two initially indeterminant results were repeated with 1 abnormal and 1 normal on repeat. The mean dense granule per platelet for the cohort was 2.68 (standard deviation [SD] 1.4) dg/pl. The mean dense granules per platelet was 3.9 dg/pl (range 1.8 - 5.47) for subjects with normal PEM results and 1.97 dg/pl (range 0 - 3.39) for those with abnormal results, p&amp;lt;0.001. Most ISTH-BATs were retrospectively calculated from clinical documentation (71/77, 92%). The mean ISTH-BAT for the cohort was 3.6 (SD 2.2) and 50/77 (65%) had an elevated ISTH-BAT score for age and gender. There was no correlation between the ISTH-BAT score and dg/pl (Pearson's r=0.17, 95% CI: -0.60 - 0.379, p=0.15), (Figure 1). There was a weak correlation between dg/pl and ISTH-BAT for female gender (Pearson's r=0.39, 95% CI: 0.105 - 0.611, p=0.009) that is not present with male gender (Pearson's r= -0.057, 95% CI: -0.404 - 0.303, p=0.759). There was no difference between the mean dense granules per platelet for those with a normal ISTH-BAT (2.5 dg/pl, 95%CI: 1.79 - 3.22) and an abnormal ISTH-BAT (2.8 dg/pl 95% CI: 2.45 - 3.10), p=0.48. Similarly, there was no association between ISTH-BAT and PEM results as a binary variable, based on reference lab normal versus abnormal result (chi-squared p=0.22). Seventy-three platelet function tests were performed in 74% (57/77) of the cohort. The majority (43/57, 75%) had only one platelet function test. Most were whole blood impedance lumi-aggregometry (WBILA) (65/73, 89%); 8 were light transmission aggregometry. The first platelet function test was abnormal in 42% (24/57) of those tested. In the 49 subjects with WBILA as their first test, the most common abnormality was ADP secretion (N=20). ADP secretion values are not correlated with dg/pl (Spearman's r=0.28, p=0.05). At least one set of VWF tests were sent in 79% of the cohort (61/77). Two subjects were diagnosed with VWD, one of whom had a reported abnormal PEM result (2.96 dg/pl) and an ISTH-BAT of 7. The other had a normal EM result (4.38 dg/pl) and an ISTH-BAT of 4. Conclusions:There was no association between platelet EM results and bleeding phenotype by ISTH-BAT in the overall pediatric cohort, however there was a weak correlation between bleeding score and dg/pl in female gender. There was also no correlation between dg/pl and ADP secretion. Future work will focus on the utility of platelet EM testing in pediatrics and identifying subpopulations who may benefit from this test.

Utility of the international society on thrombosis and hemostasis-bleeding assessment tool in the diagnosis of patients who suspected of platelet function disorders.

The ISTH-BAT is a structured bleeding assessment tool to record and help diagnose patients with possible bleeding disorders. However, a few studies evaluated the utility of ISTH-BAT in diagnosing patients with platelet function defects (PFDs). In this study, we evaluated the diagnostic utility of ISTH-BAT in predicting PFDs among patients suspected of PFDs. Forty patients suspected of PFDs and 21 normal healthy controls were evaluated by the ISTH-BAT scoring system, light transmission aggregometry (LTA), ATP-releasing assays (lumi-aggregometry), and expression of CD62P for diagnosis of PFDs. Among 40 patients suspected of PFDs, 10 were diagnosed as PFDs using lumiaggregometry and CD62P. The ISTH-BAT score in patients suspected of PFDs [(6, interquartile range (IQR) 1-8] and patients with PFDs was significantly higher than the control group (0; IQR 0-0) ( P < 0.001). Receiver operating characteristic curves indicate that ISTH-BAT is not able to discriminate patients with PFDs from those without PFDs (areas under the curve of 0.620 (95% confidence interval 0.415-0.825). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the ISTH-BAT in predicting the presence of PFDs, respectively, were 40, 73.3, 33.3, and 78.6% in the cut-off ISTH-BAT at least 4 in adult men, at least 6 in adult women, and at least 3 in children (age < 18). The ISTH-BAT scoring system has good discriminatory power in diagnosing patients with PFDs from healthy controls but is ineffective in differentiating them from those without PFDs.

PB0553 Role of International Society of Thrombosis and Hemostasis-Bleeding Assessment Tool, RICOF, ROTEM, and APTT-Clot wave form Analysis (CWA) in Evaluation of Patients with Bleeding of Unknown Cause (BUC)

PB0553 Role of International Society of Thrombosis and Hemostasis-Bleeding Assessment Tool, RICOF, ROTEM, and APTT-Clot wave form Analysis (CWA) in Evaluation of Patients with Bleeding of Unknown Cause (BUC)

The ISTH-BAT score and outcomes after endometrial ablation in women with heavy menstrual bleeding.

The International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT), is used during the diagnostic workup of bleeding disorders. Data on ISTH-BAT scores in women with heavy menstrual bleeding (HMB) undergoing endometrial ablation (EA) could be essential in optimizing HMB counselling. To investigate the postsurgical incidence of amenorrhea, dysmenorrhea, quality of life, re-intervention after EA, and ISTH-BAT score. This study included women who have undergone EA because of HMB. During a follow-up of 2 to 5 years, ISTH-BAT, pictorial blood assessment chart (PBAC), and Short Form-36 survey (SF-36) were administered. At 10 years of follow-up surgical re-interventions were evaluated. Seventy-one women were included of whom 77% (n=55) had an ISTH-BAT score<6, versus 23% (n=16) ISTH-BAT score ≥6 (mean age 46.3versus 42.3, p=0.004). In the ISTH-BAT ≥6 group versus<6 group, amenorrhea occurred in 63% (10/16) versus 82% (45/55) (p=0.111), dysmenorrhea in 38% (6/16) versus 18% (10/55) (p=0.111), and surgical re-intervention in 19% (3/16) versus 25% (14/55) (p=0.582). SF-36 item (Bodily) pain was lower in the ISTH-BAT ≥6 group versus <6 (median score 58.7vs. 80.0, p=0.104). An ISTH-BAT score ≥6 may be related to a lower amenorrhea incidence and higher dysmenorrhea rate after EA.

High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study

BackgroundHeavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce. ObjectivesTo analyze the prevalence, severity, and treatment of HMB in Dutch women with an RBD. MethodsThe Rare Bleeding Disorders in the Netherlands (RBiN) study included 263 patients with an RBD from all 6 hemophilia treatment centers (October 2017-November 2019). In this analysis, data of 111 women aged ≥16 years were studied. According to the International Society on Thrombosis and Haemostasis bleeding assessment tool, HMB symptoms were scored from 0 (no/trivial) to 4 (severe symptoms requiring medical intervention). HMB was defined as a score ≥1. Age at RBD diagnosis was extracted from patient files. ResultsHMB was reported by 80% of women (89/111) and was more prevalent in women with a fibrinolytic disorder (33/35; 94%) than in women with a coagulation factor deficiency (56/76; 74%) (P = .011). Of the 89 women with HMB, 82% (n = 73) ever required treatment. Multiple treatment modalities were frequently used, both in severe and mild deficiencies. Hormonal treatment was mostly used (n = 64; 88%), while antifibrinolytics were prescribed less frequently (n = 18; 25%). In women with HMB since menarche (n = 61; 69%), median age at RBD diagnosis was 28 years (IQR, 14-41). ConclusionHMB is common in women with RBDs. Women with mild deficiencies also frequently reported HMB. Only a minority of women were treated with hemostatic agents. A significant diagnostic delay was observed after the onset of HMB symptoms.

Characterization of bleeding symptoms in Ehlers–Danlos syndrome

BackgroundEasy bruising is included as a major or minor criterion for the classification of multiple types of Ehlers–Danlos syndrome (EDS). Despite a longstanding recognition of the association between EDS and bleeding, we still lack a definitive understanding of the frequency, severity, and types of bleeding complications in patients with EDS. ObjectivesTo evaluate hemorrhagic symptoms using the International Society of Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT) in a cohort of patients with defined types of EDS. MethodsWe utilized the ISTH-BAT to characterize hemorrhagic symptoms and their severity in a cohort of 52 patients with classical, classical-like, hypermobile, or vascular EDS and a matched group of 52 healthy control subjects. ResultsThe mean ISTH-BAT score was 0.1 for healthy subjects and 9.1 for patients with EDS (p < .0001). An abnormal ISTH-BAT score was observed in 32 of 52 (62%) patients with EDS and 0 of 52 healthy controls (p < .0001). The most frequent bleeding symptoms were bruising, muscle hematomas, menorrhagia, epistaxis, bleeding from the oral cavity, and bleeding after tooth extraction. Menorrhagia that was life-threatening or required surgery was reported in 7 of 52 (14%) patients with EDS. ConclusionPatients with multiple types of EDS exhibit a wide range of bleeding symptoms ranging from mild to life-threatening episodes.

Assessing Bleeding Symptoms in Pediatric Patients With Generalized Joint Hypermobility.

To assess bleeding symptoms in patients with generalized/benign joint hypermobility (GJH), compare bleeding scores to healthy historical pediatric controls, and determine whether a correlation exists between Beighton scores and bleeding scores. Patients with GJH ages 6-21 years seen by the rheumatology department at Nationwide Children's Hospital in Columbus, Ohio were eligible. Participants/guardians completed the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, a validated questionnaire defining the presence, severity, and frequency of bleeding symptoms. Scores of ≥3 have been associated with an underlying bleeding disorder in pediatric patients. Eighty-one patients agreed to participate. The median age was 13 years (interquartile range 10-16 years), and the mean Beighton score was 6.3 (range 4-9). Commonly observed bleeding symptoms were oral bleeding (74%), easy bruising (59%), and bleeding with minor wounds (42%). Mean and median bleeding scores were 5.2 and 4, respectively, and were significantly higher than reported bleeding scores in pediatric controls, defined as those without bleeding symptoms or a previously diagnosed bleeding disorder (P < 0.001). Although 75% of patients (95% confidence interval 64-84) had an abnormal bleeding score, only 12.3% were previously assessed by hematology for bleeding symptoms. Among patients with GJH, higher Beighton scores were not associated with higher bleeding scores (Spearman's correlation -0.08). In a cohort of pediatric patients with GJH, three-fourths of participants had abnormal bleeding scores, with the mean bleeding score significantly elevated compared to healthy controls. We propose that screening for bleeding symptoms be integrated into routine care for GJH patients, with referral to hematology for patients with bleeding concerns.

Bleeding phenotype in nonsevere hemophilia by International Society on Thrombosis and Haemostasis bleeding assessment tool, bleeding frequency, and the joint status

BackgroundAlthough the phenotype of severe hemophilia has been well studied, there are still knowledge gaps in nonsevere hemophilia. ObjectivesThe objective of this study was to characterize the clinical bleeding phenotype in nonsevere hemophilia and its association with different factor VIII/IX assessments. MethodsThis was a cross-sectional, multicenter study to investigate the bleeding phenotype in adults with nonsevere hemophilia by the number of bleeding and joint bleeding in the past 5 years, a joint score, and the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT). Factor levels were analyzed by 1-stage (lowest in history and at study inclusion) and chromogenic assay (at study inclusion). Patients were enrolled between March 2015 and May 2019. ResultsOf the 111 patients (86 with mild and 25 with moderate hemophilia), 57 patients (54.8%) reported any bleeding and 24 (23.1%) any joint bleeding in the past 5 years. A joint score ≥1 was found in 44 patients (41.9%), an ISTH-BAT ≥4 in 100 patients (90.1%), and an ISTH-BAT joint item ≥1 in 50 patients (45.0%). Within the ISTH-BAT, muscle and joint bleeds showed the largest difference between mild and moderate hemophilia. The lowest factor VIII/IX level in patients’ history was best associated with bleeding outcomes. Factor was inversely associated with joint bleeds (incidence rate ratio 0.88; 95% CI, 0.79-0.98), joint score, and ISTH-BAT (odds ratios from proportional odds ordinal logistic regression 0.92; 95% CI, 0.87-0.97; and 0.89; 95% CI, 0.86-0.93, respectively). ConclusionThe occurrence of joint bleeding differentiated persons with mild and moderate hemophilia. The ISTH-BAT and lowest factor in patients’ history provided valuable information of the bleeding phenotype in nonsevere hemophilia.

Assessing the bleeding severity in patients with type I von Willebrand using the International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) questionnaire

Abstract Background In the recent decade, bleeding evaluation methods have evolved to standardize the severity of bleeding symptoms in a uniform manner. In 2010, the International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) was developed and validated. Aim and objectives The aim of the study was to evaluate bleeding score (BS) in Egyptian patients with von Willebrand disease (VWD) type I and correlate it with laboratory parameters. Patients and methods This cross-sectional cohort study was conducted at Assiut University Hospital. It included 100 participants that were divided into 49 patients with type I VWD and 51 healthy participants with no known problem with bleeding or bruising. The duration of the study was ~12 months. Results Study revealed that there was significant relation between BS severity and laboratory parameters such as level of von Willebrand factor: Ag (P=0.02) while there was no significant relation between BS and sex (P=0.390). By using receiver operating characteristic curve analysis, ISTH-BAT BS can detect type I VWD patients in total with excellent accuracy (98%), area under the curve was 0.989 with sensitivity and specificity of 96 and 100%, respectively (P&lt;0.001). Conclusion The ISTH-BAT BS is designed to reflect the severity of bleeding. Our results demonstrate the inherent variability of this bleeding pattern. We also found that the ISTH-BAT BS has high sensitivity and specificity to detect type I VWD patients in total with excellent accuracy.

Joint Status and Bleeding Phenotype Characterization in Severe and Non-Severe Hemophilia a and B

Introduction: Persons with hemophilia (PwH) A and B are known to have variable bleeding phenotypes and may have joint bleeding that is less clinically apparent. In recent years, musculoskeletal ultrasound (MSKUS) has become an established modality useful for evaluating joint status. Further, determination of individual bleeding phenotype can be challenging, but clinical tools including the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT), self-BAT, and the Beighton Hypermobility Score (BHS) have been developed. Methods: We hypothesize that presence and degree of joint disease, evaluated with MSKUS and physical assessment scoring, will correlate with severity of bleeding phenotype as characterized through clinical history, BAT assessment, and presence of joint hypermobility in PwH A and B. This will be accomplished through assessing baseline joint status and disease progression over time with MSKUS, as well as through use of the ISTH-BAT, self-BAT, and assessment of hypermobility with the BHS. Up to 100 individual subjects with severe, moderate, or mild hemophilia A or B will be enrolled and assessed at baseline and annually during the study period at our institution. Correlation of joint status with BHS and BAT scores will be analyzed with the generalized estimating equation (GEE) and other statistical methods. Results: Thus far, 15 male patients have been enrolled (Table 1). All moderate and severe hemophilia patients are on prophylactic therapies for bleed prevention, and 3 patients have history of inhibitors. Target joints were reported only in severe PwH. MSKUS measurements were completed using the JADE protocol1. Patient enrollment remains ongoing. Discussion: Knowledge pertaining to joint status and bleeding phenotype is PwH A and B is limited. This pilot study will assess the presence and degree of joint disease, evaluated with MSKUS and physical assessment scoring, and its correlation with severity of bleeding phenotype as characterized through clinical history, BAT assessment, and presence of joint hypermobility in PwH hemophilia A and B. The results will be used to justify a larger, multicenter study to expand understanding of joint status and bleeding phenotype in PwH.

Outcomes and management of pregnancy in women with bleeding disorder of unknown cause

BackgroundPatients with a bleeding tendency with normal laboratory tests have been described as having an unclassified bleeding disorder or bleeding disorder of unknown cause (BDUC). There are very little data available on how to manage pregnancy. ObjectivesTo study management and outcomes of these patients at four United Kingdom hemophilia comprehensive care centers. MethodsRetrospective case note review from 2010–2020. ResultsSixty deliveries in 36 patients were recorded. The median International Society on Thrombosis and Haemostasis bleeding assessment tool score was 9. In 54 cases for which data were available, the odds ratio for post partum hemorrhage (PPH) was 6.3 for no primary hemostatic prophylaxis versus prophylaxis (95% confidence interval 1.2–34.2, p < .05); 7/9 (78%) versus 16/45 (36%) PPH incidence for the groups, respectively. Hemostatic prophylaxis was with tranexamic acid but some patients received desmopressin or platelet infusions. Secondary PPH was seen in 5/60 (8%) of cases. No neonatal bleeding complications or maternal thromboembolic complications were noted. Avoidance of regional anesthesia and fetal delivery precautions were commonly advised, but in the small number of cases in which they occurred no complications were noted. ConclusionsDespite hemostatic prophylaxis PPH was commonly seen. Further prospective studies of BDUC patients are required to determine optimal management in pregnancy as well as determine the pathophysiological basis of bleeding.

РЕЗУЛЬТАТЫ РЕТРОСПЕКТИВНОГО СРАВНИТЕЛЬНОГО АНАЛИЗА ПРОЯВЛЕНИЙ И ВЫРАЖЕННОСТИ ГЕМОРРАГИЧЕСКОГО СИНДРОМА У ДЕТЕЙ С ТРОМБАСТЕНИЕЙ ГЛАНЦМАНА

Glanzmann thrombastenia (GT) refers to a rare and severe pathology of platelets and causes frequent bleeding episodes in children and adults, miscarriage and intracranial hemorrhage in fetuses and newborns from mothers with GT. Objective of the study: to assess the severity of hemorrhagic syndrome in children diagnosed with GT and to conduct a comparative assessment of bleeding in patients with other hereditary thrombocytopathies and von Willebrand disease (VWD). Materials and methods of research: a retrospective analysis of 25 clinical observations of children diagnosed with GT (8 boys and 17 girls) was carried out; the median age at the time of treatment was 5 years, which were observed at the Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology in 2015–2020. Bleeding manifestations were assessed using the Pediatric Bleeding Questionnaire (PBQ) and the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH BAT) standard bleeding scales. The analysis of publications presented in the international databases SCOPUS and PUBMED over the past 10 years on modern approaches to GT therapy has been performed. Results: the diagnosis of GT was established in 25 children, the median PBQ score was 7 points compared with the group of children with thrombocytopathies 3 points [IQR 7 (5,5; 10,5) versus 3 (2; 5), p&lt;0,00001] and VWD 4 points [IQR 7 (5,5; 10,5) versus 4 (2; 5,25), p&lt;0,00001]. On the ISTH BAT scale in children with GT 8 points, in groups with thrombocytopathies 3 points [IQR 8 (6,5; 11,5) versus 3 (2; 5), p&lt;0,00001] and VWD 4 points [IQR 8 (6,5; 11,5) versus 4 (2; 5,25), p&lt;0,00001]. In 23 (92%) children, episodes of bleeding required periodic visits for emergency medical care, in 17 (68%) resulted in anemization and iron deficiency. Compared with the group of children with hereditary thrombocytopathies and VWD patients with GT had more severe and frequent bleeding symptoms, which required seeking medical attention. Conclusion: GT is a rare, severe disease in which bleeding is systemic, leads to anemization, causes frequent hospitalizations, which greatly reduces the quality of life of patients.

Phenotype and genotype analysis of patients with severe factor XI deficiency in Shaanxi Province, China.

Congenital coagulation factor XI (FXI) deficiency is a rare bleeding disorder with a heterogeneous haemorrhagic phenotype and various hotspot gene mutations associated with race and geography. Studies on FXI deficiency in Shaanxi Province, China, are scarce. In this study, seven patients with severe FXI deficiency and several family members were analysed. The International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) was applied to assess bleeding symptoms. FXI activity was determined using a one-stage method, and the FXI antigen was measured by enzyme-linked immunosorbent assay. Targeted capture next-generation sequencing and Sanger sequencing were applied to detect FXI gene mutations. The bleeding phenotype varied, although none of the participants had a history of spontaneous bleeding. One maternal received replacement therapy during the perinatal period, one female patient presented with menorrhagia, one male patient experienced severe postoperative bleeding and others were asymptomatic. Family members with heterozygous mutations were all asymptomatic. The FXI activity of all the patients ranged from less than 1 to 3.1 IU/dl, and a synchronous decrease in the FXI antigen was observed. Two missense mutations (p. Gly350Glu and p. Cys482Trp), one nonsense mutation (p. Gln384∗) and one novel frameshift mutation (p. Ser225Phefs∗16) were detected. The bleeding manifestations and severity of severe FXI deficiency varied and were not related to its activity. Three reported mutations and one novel frameshift mutation were identified, thus extending the mutation spectrum of FXI deficiency.

Contribution of Select ISTH-BAT Subscores to the Total Score in Type 1 VWD

Background:von Willebrand Disease (VWD) is the most common inherited bleeding disorder with partial quantitative deficiency in von Willebrand Factor (VWF); Type 1 comprises 80% of VWD. Clinical manifestations include mucocutaneous bleeding, prolonged bleeding after surgery or injury and excessive menorrhagia in females which have also been reported in normal subjects. A diagnosis of Type 1 VWD is based upon reduced plasma VWF, abnormal mucocutaneous bleeding symptoms and usually a family history of bleeding and VWD. Evaluating abnormal bleeding symptoms involves a detailed bleeding history, which can be quite subjective and time consuming. To address these challenges, the Vicenza-based Bleeding Assessment Tool (BAT) was developed as a validated score and has evolved into the current International Society on Thrombosis and Haemostasis-Bleeding Assessment Tool (ISTH-BAT). A large multi-center NIH supported study (The Zimmerman Program for the Molecular and Clinical Biology of VWD), began in 2005 to correlate clinical laboratory testing, bleeding severity determined by the ISTH-BAT and genetic variability in VWD. In this current study, we investigated which bleeding symptoms were most sensitive in applying the ISTH-BAT to the diagnosis of Type I VWD.Methods:Subjects were enrolled in the Zimmerman Program . Each symptom in the validated ISTH-BAT questionnaire was scored from 0-4 (no symptoms to symptom intervention) and included epistaxis, bruising, oral bleeding, hematuria, gastrointestinal (GI) bleeding, head bleeding, hemarthrosis, hematoma and prolonged bleeding with minor wounds, tooth extraction, surgery, menstruation and child birth. Other scored bleeding symptoms included bleeding at circumcision, excessive umbilical stump bleeding, venipuncture bleeding, vacuum extraction delivery bleeding, ovulatory bleeding and cephalohematoma. The scores of each symptom were analyzed in both healthy controls and subjects diagnosed with Type 1 VWD. Only subjects with VWF antigen (VWF:Ag) and/or VWF ristocetin cofactor activity (VWF:RCo) <30 IU/dL were considered in the comparative analysis. VWF levels were performed by a central laboratory, including VWF:Ag, VWF:RCo, VWF propeptide (VWFpp) and VWF collagen binding with type III collagen (VWF:CB). Statistical analysis included Mann-Whitney test, Chi-square or a Fisher's exact test, Pearson correlations and Spearman correlations. Results were considered significant for a two-sided p-value <0.05. A regression analysis was performed to examine which subscores contributed the most to the total score of the ISTH-BAT.Results:Analysis included 383 subjects (Female=262, Male=121) enrolled in the Zimmerman Program . Of these subjects, 244 were healthy controls (mean age of 38.93 [range 10-73 years of age]) and 139 had Type 1 VWD (mean age of 19.46 [range 1-76 years of age]). Within the Type 1 subjects, there were more females >12 years of age (no gender difference < 12 years of age) and greater number of Caucasians and younger subjects. Type 1 VWD subjects scored significantly higher than the healthy control group in both ISTH-BAT total scores (p<0.0001) as well as all subscores (p<0.001). In comparing bleeding symptoms from healthy controls with Type 1 VWD subjects: epistaxis 4% vs 46%, bruising 16% vs 64%, minor wound bleeding 1% vs 42%, oral bleeding 3% vs 35%, tooth extraction bleeding 3% vs 18%, GI bleeding 3% vs 11%, hematuria 0% vs 11%, surgical bleeding 4% vs 23%, menstrual bleeding 60% vs 85%, bleeding after delivery 2% vs 12%, other bleeding 0% vs 11% (47% were circumcision bleeding), head bleeding 0% vs 4%, hemarthrosis 0% vs 11%, and hematoma 0% vs 7%. Regression analysis revealed that epistaxis, bruising, excessive bleeding with minor wounds, oral bleeding, and menstrual bleeding subscores contributed the most to the ISTH-BAT total score (p<0.016).Conclusion:The ISTH-BAT currently is strongly predictive of bleeding symptoms in the diagnosis of Type 1 VWD. Though all ISTH-BAT subscores correlated with a diagnosis of Type 1 VWD, some subscores contributed more significantly to the total score than others and were more prevalent than in normal subjects. Accordingly, the sensitivity and specificity of ISTH-BAT subscores are critical to the assessment of bleeding in the diagnosis of Type 1 VWD. DisclosuresFlood:Shire: Consultancy; CSL Behring: Consultancy. Gill:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. James:CSL Behring: Research Funding; Shire: Research Funding; Bayer: Research Funding.