The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner

Background: Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions. Methods: The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice. Results: The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times. Conclusions: Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury.

STUDY OF DIAGNOSTIC HYSTEROSCOPY IN PERI AND POSTMENOPAUSAL WOMEN WITH ABNORMAL UTERINE BLEEDING

Background:Abnormal uterine bleeding is dened as bleeding from uterus that differs from that of usual normal menstrual bleeding, in frequency of occurrence or in amount or in alteration of ow. The advantages of hysteroscopy as an accurate diagnostic technique are that it not only allows direct visual observation of pathology but also provides a means to sample the site, most likely to yield positive results. The present study was conducted to study the role of Hysteroscopy in abnormal uterine bleeding in Peri and Post-menopausal women at a tertiary care hospital. Material And Methods: Present study was single-center, prospective, Cross sectional study, conducted in women age ≥40years with heavy menstrual bleeding, prolonged bleeding, frequent menstruation, intermenstrual bleeding and post coital bleeding, Post-menopausal bleeding. Hysteroscopy was performed preferably in post-menstrual phase or post bleeding phase with a standard 4mm hysteroscope(Stryker) with a 30 degree fore-oblique lens. Procedure was performed under IV sedation with normal saline as distention media. Results: In present study, majority of the subjects (n=28) i.e. 36.8% presented with heavy menstrual bleeding followed by prolonged bleeding (32.8%), post- menopausal bleeding (21%), frequent menstruation (7.89%) and inter-menstrual bleeding (1.3%). On hysteroscopy normal ndings were present in 32 subjects (42%) followed by hyperplasia (17.1%), atrophic endometrium (13.1%), submucous broid (14.4%), endometrial growth (2.96%) & broid polyp (1.36%). Histopathology examination noted Proliferative endometrium (31.5%), secretory (10.5%), disordered proliferative phase (1.3%), simple hyperplasia (18.4%), complex hyperplasia with atypia (1.3%), submucous broid (14.4%), endometrial polyp (34.2%), atrophy (13.1%), broid polyp (1.34%) and malignancy (3.96%). Sensitivity, Specicity, PPV, NPV values were 100 % except for sensitivity for endometrial growth (66.7 %). p Value was highly signicant for all parameters (p <0.0001) Conclusion: Hysteroscopy has a better diagnostic accuracy as it provides the option of see and treat which is recommended for peri and post-menopausal women with AUB.. The intracavitary lesions (submucous leiomyomas, polyps, endometrial growth are) better diagnosed on hysteroscopy

Preprocedural Hypertension Is Not a Risk Factor for Postoperative Bleeding following Image-Guided Core Needle Breast Biopsy

Objective. To evaluate the association between preprocedural hypertension and the risk of prolonged bleeding following image-guided core needle breast biopsy in nonpregnant/nonlactating women. Methods. A single institution-based, retrospective cohort study of 400 women who underwent image-guided core needle breast biopsy was conducted. Males and pregnant and lactating women were excluded. Preprocedural systolic or diastolic blood pressure greater than 140 or 90 mm of Hg, respectively, was defined as hypertension. Prolonged bleeding was defined >15 minutes of local, manual pressure required to achieve hemostasis following the biopsy. Severe bleeding complications defined as clinical significant hematoma formation, prolonged bleeding requiring an ER visit, hospitalization, or surgical intervention were also recorded. Results. The difference in the mean time for which manual pressure was held after biopsy for patients with and without preprocedural hypertension was not statistically significant (13 ± 7 vs. 13 ± 8 minutes, respectively, P = 0.856). There was no difference in the number of patients requiring manual postoperative pressure >15 minutes between those with preprocedural hypertension and the normotensive patients (13% vs. 12%, respectively, P = 0.765). Bivariate analysis demonstrated statistically significant association between prolonged bleeding and current antithrombotic or antiplatelet medication use ( P = 0.010), the use of stereotactic guidance ( P = 0.019), and a tethered vacuum-assisted device ( P = 0.045). The use of a tethered vacuum-assisted biopsy device was the only variable associated with prolonged bleeding in the multivariate model ( P = 0.044). Conclusion. Preprocedural hypertension is not a risk factor for prolonged bleeding following image-guided core needle breast biopsies in nonpregnant/nonlactating women.

Severe haemophilia A in a preterm girl with Turner syndrome: case report – a diagnostic and therapeutic challenge for a paediatrician (Part 2)

Background Haemophilia A is an X-linked genetic condition which manifests itself mainly in male children in the first 2 years of life, during gross motor skill development. This disorder is rare in females. The clinical manifestation of severe haemophilia in preterm infants poses a great challenge to the therapeutic team. As extreme prematurity is linked to an increased risk of central nervous system or gastrointestinal bleeding, a well-informed and balanced treatment from the first days of life is crucial to prevent long-term damage. Haemophilia is most commonly caused by inheriting defective genes, and can also be linked to skewed X inactivation and Turner syndrome. The coincidental occurrence of haemophilia A and Turner syndrome is extremely rare, with only isolated cases described to date. Hence, a multidisciplinary approach is needed. Case presentation The authors report on a preterm girl (gestational age 28 weeks) diagnosed with haemophilia and Turner syndrome. The first manifestation of haemophilia was prolonged bleeding from injection sites on the second day of life. Indeterminate aPTT and factor VIII level < 1% confirmed the diagnosis of haemophilia A. Dysmorphic features which did not match the typical clinical picture of haemophilia, the female sex, and a negative paternal family history led to the diagnosis of Turner syndrome. While in hospital, the girl received multiple doses of recombinant factor VIII in response to prolonged bleedings from the injection sites and from a nodule on the girl’s head, and before and after retinal laser photocoagulation. No central nervous system or abdominal cavity bleeding was observed. The substitutive therapy was complicated by the development of factor VIII inhibitor (anti-factor VIII (FVIII) antibodies). Treatment was continued with recombinant factor VIIa. This article aims at demonstrating the complexity of the diagnostics and treatment of a preterm child with two genetic disorders. Conclusions Haemophilia should always be considered in the differential diagnosis of prolonged bleeding, even in patients with a negative family history. In the case of coinciding atypical phenotypic features, further diagnostics for another genetic disease are recommended. Infant care should follow current care standards, while considering certain individual features.

Prolonged Bleeding due to Hirudotherapy (Medicinal Leech Therapy)

Medicinal leech therapy is a form of complementary medicine that has long been practised and is gaining popularity in recent years for various illnesses and surgical applications. However, leech saliva contains proteins with anticoagulant properties that can lead to prolonged bleeding from the bite area. We report a case of a 35-year-old male who presented to the Emergency Department due to prolonged bleeding from a leech-bite wound. He did not have any significant past medical history or medication history. He had undergone medicinal leech therapy for chronic back pain. After the therapy, he noted that the bleeding did not stop after 7 hours (which normally stops within 30 minutes) and decided to seek treatment. There were wounds over his lower back and both feet, which were all clean. The wound over the lower back had persistent oozing. We applied topical adrenaline and manual compression on the wound, and eventually the bleeding reduced and stopped. There are many suggested methods to stop bleeding from leech-bite wounds but there is scarcity of evidence regarding the superiority of any method. This is the first case report regarding bleeding complications in medicinal leech therapy in Malaysia. This report aims to raise awareness regarding the complications arising from a leech bite among the practitioners of medicinal leech therapy, the public and healthcare providers in emergency facilities. We also suggest using topical adrenaline as an alternative to help stop bleeding from leech-bite wounds.

Incidental diagnosis of haemophilia: A case report of three cases following voluntary medical male circumcision in South Africa

Introduction: Since 2007, over 15.2 million Voluntary Medical Male Circumcisions (VMMCs) have been performed in 14 sub-Saharan African countries for partial prevention of transmission of HIV. In South Africa, close to 4 million VMMCs have been conducted since the onset of the national VMMC program in 2010. Within this context, the occurrence of notifiable adverse events related to peri-operative bleeding occurs commonly. The ability to screen, diagnose, and manage these cases appropriately will mitigate associated adverse events. Aim: In this paper, we describe three cases of prolonged bleeding after VMMC procedure and propose program measures. Methods: Descriptive haemophilia case accrual at three sites implementing a PEPFAR- funded VMMC program. The cases were recruited consecutively over a 17-month period (May 2017 to September 2018). Standard laboratory tests were used to confirm diagnosis. Written assent and informed consent were obtained from each subject and their respective guardians. Results: A total number of 31 severe or moderate adverse events were reported of whom three 16-year-old clients from three different provinces in South Africa were diagnosed with Haemophilia post VMMC services during July 2018. Two clients were diagnosed with Haemophilia A and one client was diagnosed with Haemophilia B. Conclusions: Greater emphasis on training and placement of qualified health care workers for peri-operative screening as well as a high index of suspicion for pre-operative diagnosis and appropriate referral for bleeding disorders is highly recommended. Clinical VMMC protocols guiding post-operative wound management, adverse event management, active client follow-up and care need to be reinforced, with rigorous reporting. Keywords: Prolonged bleeding; Adverse events; Haemophilia; Screening; Bleeding disorders; Incidental diagnosis.

Rare Late Presentation of Severe Congenital Hemophilia A in an Adult Ugandan Soldier Following Elective Circumcision

Severe hemophilia symptoms usually start in infancy. Affected individuals require coagulation factor routinely to live a normal life. A 25-year old active-duty soldier was diagnosed with severe congenital hemophilia A after presenting with initial episode of prolonged bleeding. His case demonstrates a rare late presentation of hemophilia.

Clinical bleeding patterns and management techniques of abnormal uterine bleeding at a teaching and referral hospital in Western Kenya

Abnormal uterine bleeding (AUB) affects 30% of reproductive age women globally. However, there are limited local studies evaluating the management of these women. The diagnostic guideline using structural and functional causes of AUB adopts the PALM-COEIN criteria, namely: Polyp; Adenomyosis; Leiomyoma; Malignancy and Hyperplasia; Coagulopathy; Ovulatory dysfunction; Endometrial; Iatrogenic; and Not yet classified. This study aimed to determine the clinical bleeding patterns, adherence to PALM-COEIN diagnosis guidelines and management of AUB among women in their reproductive age. This was a cross-sectional study among 108 women with AUB aged 18–45 years was conducted at the gynaecology department of Moi Teaching and Referral Hospital in Western Kenya between April 2018 and April 2019. Their sociodemographic and clinical characteristics were collected using interviewer administered structured questionnaire and chart reviews. Adherence to diagnosis recommendations was assessed using PALM COEIN classification. Descriptive and inferential data analysis was conducted at 95% confidence interval. The median age was 30 (IQR: 22, 41) years with prolonged bleeding as the most predominant pattern at 41.7%. Bleeding patterns were significantly associated with age (p = 0.04). Only 16.7% were diagnosed as per the PALM-COEIN criteria with PALM and COEIN accounting for 60% and 40% respectively. Leiomyoma (44.5%) was the common cause of AUB. Laboratory evaluation included: pregnancy tests, full haemogram, hormonal profile and biopsy. Most (79.6%) of the women had abdominopelvic ultrasound done. Medical management was provided for 78.7% of women. Prolonged bleeding was the most common pattern with medical management preferred. There is need for in-hospital algorithms to ensure adherence to PALM-COEIN guidelines.

A randomized-controlled pilot study on the effects of naproxen for the treatment of bleeding and spotting among new Copper T 380A IUD users

Background: The most common reason women report discontinued use of the Copper T 380A (TCu380A) IUD is because of bleeding irregularities after method initiation. The objective of this study was to determine whether an over-the-counter NSAID, naproxen sodium, reduces the number of bleeding and spotting days and heavy or prolonged bleeding episodes among new users of the TCu380A IUD compared to placebo.Methods: In this double-blind pilot trial, we randomized 28 new TCu380A IUD users who reported menstrual cycle changes within 4-6 weeks after IUD placement to either naproxen 440 mg or placebo twice daily for 7 days for three consecutive 28-day cycles and one additional 28-day cycle without treatment. Participants completed a daily bleeding and other symptom diary, and monthly questionnaires. Results: Although not statistically significant, participants in the naproxen arm reported more mean number of spotting-only days during the three treatment cycles compared those in the placebo group (13.5 days (SE 5.1) vs.7.5 days (SE 1.7), respectively). Otherwise, the mean number of bleeding-only days during treatment and post-treatment and spotting-only post-treatment were similar between the groups. During each treatment cycle, fewer participants in the treatment group reported heavy bleeding compared to placebo group (30.7% fewer in cycle 2; 5.4% fewer in cycle 3). More women in the treatment group, however, reported prolonged menstrual bleeding of greater than 7 days for each cycle, although the percentage reporting prolonged bleeding decreased each consecutive treatment and post-treatment cycle (+27.5%, +19.8%, +9.1%, +4.5%, cycles 1-4 respectively). Other symptoms experienced by new TCu380A users did not differ between the study arms.Conclusions: Treatment with naproxen did not significantly reduce the number of bleeding or spotting days among new TCu380A users. Although not statistically different, proportionally fewer participants in the naproxen group reported moderate-heavy or heavy periods, but more reported prolonged menstrual bleeding compared to placebo. Participants tolerated oral naproxen use well.Trial registration: ClinicalTrials.gov: NCT02519231. Registered on August 10 2015.

Prolonged Bleeding Following Removal of Arterio-Venous Fistula Needles after Hemodialysis Therapy

Background: Bleeding at fistula sites in patients with end stage renal disease (ESRD) is a common and potentially serious complication that contributes to blood loss (anemia). This study aimed to determine the factors that influence prolonged bleeding at fistula puncture sites following removal of fistula needles.Methods: This was a descriptive cross-sectional study. We consecutively enrolled patients who underwent maintenance hemodialysis between May and October 2017 at Muhimbili National Hospital and Access Dialysis Centre in Dar es Salaam, Tanzania. A case report form (CRF) was used for data collection.Prolonged bleeding was assessed by measuring activated partial thromboplastin time (aPTT) and compression time (CT). Descriptive statistics and regression analysis were used to assess the association between factors and tease out the independent factors associated with prolonged bleeding at fistula puncture site. A two-tailed p-value <0.05 was used as a cut-off for statistical significance.Results: One hundred and fifteen patients were recruited for the study whereby 81(70.4%) of participants had elevated aPTT (> 31 seconds) and 4 (3.5%) had prolonged compression time (> 15 minutes). The mean aPTT and compression time of the participants were 42 ± 17.6 seconds and 5 ± 2.9 minutes respectively. Over half of participants 67(58.2%) had normal compression time (≤ 15 minutes). Elevated serum urea levels (> 7.4mmol/L) was the only factor significantly associated with elevated aPTT (OR=4.143 95% C.I (1.021-16.810), p=0.047).Conclusion: The findings have demonstrated that elevated serum urea levels are significantly associated with prolonged bleeding time following removal of Arterio-Venous fistula needles after completion of a hemodialysis therapy session. This study suggests that, in hemodialysis procedure where a fixed dose of heparin is generalized to all patients there is a chance of exceeding the individual’s requirements.Recommendations: Serum urea levels should be factored in when gauging the individual risk of arterio-venous fistula site bleeding for patients using heparin for anticoagulation during hemodialysis. Further studies with large sample sizes are recommended to elucidate how other predisposing factors may affect A-V fistula bleeding. Keywords: Hemodialysis, heparin, prolonged bleeding, urea reduction ratio, A-V Fistula, aPTT, Compression time, blood urea.