Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment.

INTRODUCTION: There is an unmet need to characterize the diagnosis and management of patients with an unclassified bleeding disorder (UBD). METHODS: Retrospective review of registered patients with UBD at our centre. Assessment including rotational thromboelastometry (ROTEM) and thrombin generation (TG) were used. RESULTS: A total of 124 patients were identified; 91% female. Mean age of presentation was 38.3 years. Mean bleeding score was 8.8 (standard deviation [SD] 3.8); 6.6 in men (SD 1.4) and 9.7 in women (SD 3.3), which was significantly different (P < .05). In women, after deduction of scores for menorrhagia and postpartum haemorrhage, the mean score was 6.4 which was not significantly different to the male score (P = .11). Twenty-three percent of patients have been transfused, 61% women had treatment for menorrhagia and 17% for epistaxis. TxA and desmopressin were effective at preventing bleeding in 69 procedures and 13 deliveries. TG revealed 26% patients with a long lag time and 19% with a decreased endogenous thrombin potential but no diagnostic pattern was seen. ROTEM (NATEM) was unable to characterize patients; 9% had a prolonged clot time or maximum lysis. ThromboGenomics was normal in 45 tested patients. CONCLUSIONS: We provide data which shows the bleeding score is biased towards gynaecological bleeding but which remains elevated even when the bleeding score is deducted. Tranexamic acid and desmopressin are effective as haemostatic prophylaxis but there is an urgent need for clinical trials. In conclusion, we describe the use of the bleeding score in these patients and phenotype, diagnosis (including ThromboGenomic testing) and management with practice recommendations.

S-allyl cysteine ameliorates cyclophosphamide-induced downregulation of urothelial uroplakin IIIa with a concomitant effect on expression and release of CCL11and TNF-α in mice.

BACKGROUND: The aim of this study was to evaluate the modulatory effect of S-allyl cysteine against cyclophosphamide-induced changes in uroplakin IIIa, CCL11 and TNF-α. METHODS: Mice were treated with cyclophosphamide (200mg/kg×7 d, ip). S-allyl cysteine (150mg/kg×7d, ip), and comparator compound mesna (40mg/kg×7d, ip) were administered 1h before and 4h after each cyclophosphamide dose. The urinary bladder was analysed for mRNA and protein changes in uroplakin IIIa (UPIIIa), CCL11 and TNF-α and histopathological findings. RESULTS: Cyclophosphamide caused hemorrhagic cystitis formation and downregulation of UPIIIa. These changes were accompanied by upregulation of CCL11 and TNF-α. S-allyl cysteine attenuated these changes including protection at histological level. Mesna which was used as a comparator drug also showed protection. However, relatively S-allyl cysteine showed a stronger protective effect than mesna. CONCLUSION: These findings highlight a correlation between downregulaion of UPIIIa and enhanced production of inflammatory biomarkers and protective effects of S-allyl cysteine which has been reported to be a potent uroprotective agent. The present study strengthens its role which could be clinically exploited in chemotherapy regimen.

Erythrocyte-Derived Nanoparticles as a Theranostic Agent for Near-Infrared Fluorescence Imaging and Thrombolysis of Blood Clots.

Ischemic stroke occurs when a blood clot obstructs or narrows the arteries that supply blood to the brain. Currently, tissue plasminogen activator (tPA), a thrombolytic agent, is the only United States Food and Drug Administration (FDA)-approved pharmacologic treatment for ischemic stroke. Despite its effective usage, the major limitation of tPA that stems from its short half-life in plasma (≈5 min) is the potential for increased risk of hemorrhagic complications. To circumvent these limitations, herein, the first proof-of-principle demonstration of a theranostic nanoconstruct system derived from erythrocytes doped with the FDA-approved near-infrared (NIR) imaging agent, indocyanine green, and surface-functionalized with tPA is reported. Using a clot model, the dual functionality of these nanoconstructs in NIR fluorescence imaging and clot lysis is demonstrated. These biomimetic theranostic nanoconstructs may ultimately be effective in imaging and treatment of blood clots involved in ischemic stroke.

Craniosynostosis and Guanine Nucleotide-binding Protein Alpha Stimulating Mutation: Risk of Bleeding Diathesis and Circulatory Collapse in Patients Undergoing Cranial Vault Reconstruction.

Reconstruction of the craniosynostosis deformity is a relatively safe operation with low overall complication risks. Despite expected risk of significant blood loss, life-threatening bleeding is relatively rare, and there is a low incidence of reported deaths in the literature. Several modalities have been described for perioperative mitigation of blood loss and transfusion requirements. Due to the low overall risk of life-threatening bleeding and circulatory collapse, it is judicious that any potential causes of such unusual but potentially significant fatal bleeding complication be evaluated and reported to increase awareness for craniofacial surgeons treating these conditions. In this report and literature review, the authors present a highly unusual patient with significant bone bleeding and circulatory collapse in a metopic craniosynostosis patient with guanine nucleotide-binding protein alpha stimulating (GNAS) mutation; perform a literature review regarding bleeding diathesis in craniosynostosis patients with GNAS mutations; and suggest guidelines to potentially prevent mortality in such patients.

Diagnostic laboratory for bleeding disorders ensures efficient management of haemorrhagic disorders.

Haemorrhagic disorders like Postpartum haemorrhage and Dengue haemorrhagic fever are life threatening and requires an active and efficient transfusion service that could provide the most appropriate blood product which could be effective in managing them. This would essentially require prompt identification of the coagulopathy so that the best available product can be given to the bleeding patient to correct the identified haemostatic defect which will help control the bleeding. This would only be possible if the transfusion service has a laboratory to correctly detect the haemostatic defect and that too with an accuracy and precision which is ensured by a good laboratory quality assurance practices. These same processes are necessary for the transfusion services to ensure the quality of the blood products manufactured by them and that it contains adequate amounts of haemostasis factors which will be good to be effective in the management of haemorrhagic disorders. These issues are discussed in detail individually in the management of postpartum haemorrhage and Dengue haemorrhagic fever including when these can help in the use of rFVIIa in Dengue haemorrhagic fever. The requirements to ensure good-quality blood products are made available for the management of these disorders and the same have also been described.

Venomous snakebites in children in southern Croatia.

This retrospective study represents observation of 160 children and adolescents aged up to 18 years that experienced venomous snakebites in southern Croatia and were treated in the Clinical Department of Infectious Diseases in the University Hospital Centre Split from 1979 to 2013. The main purpose of this research was to determine the epidemiological characteristics, clinical presentation, local and general complications, and received treatment. Most bites occurred during warm months, from early May to late August (80%), mostly in May and June. Upper limb bites were more frequent (59%) than lower limb bites (40%). Out of the total number of poisoned children, 24% developed local, and 25% general complications. The most common local complications were haemorrhagic blisters that occurred in 20% children, followed by compartment syndrome presented in 7.5% patients. The most dominated general complication was cranial nerve paresis or paralysis, which was identified in 11.2% patients, whereas shock symptoms were registrated in 7% children. According to severity of poisoning, 9.4% children had minor, 35% mild, 30.6% moderate, and 24.4% had severe clinical manifestation of envenomation. Only one (0.6%) child passed away because of snakebite directly on the neck. All patients received antivenom produced by the Institute of Immunology in Zagreb, tetanus prophylaxis as well, and almost all of them received antibiotics, and a great majority of them also received corticosteroids and antihistamines. Neighter anaphylactic reaction nor serum disease were noticed in our patients after administrating antivenom. A total of 26% children underwent surgical interventions, and incision of haemorrhagic blister was the most common applied surgical treatment, which was preformed in 15.6% patients, while fasciotomy was done in 7.5% subjects. All of our surgically treated patients recovered successfully.

International warfarin genotype-guided dosing algorithms in the Turkish population and their preventive effects on major and life-threatening hemorrhagic events.

AIM: To determine the accuracy of international warfarin pharmacogenetic algorithms developed on large multiethnic cohorts (comprising more than 1000 subjects) to predict therapeutic warfarin doses in Turkish patients. MATERIALS & METHODS: We investigated two Turkish warfarin-treated cohorts: patients with no history of hemorrhagic or thromboembolic event and patients with major and life-threatening hemorrhagic events. RESULTS: International pharmacogenetic algorithms showed good performances in predicting the therapeutic dose of patients with no history of bleedings, but they did not significantly detect the incorrect warfarin dose of patients with major and life-threatening hemorrhagic events. CONCLUSION: Although genetic information can predict the therapeutic warfarin dose, the accuracy of the international pharmacogenetic algorithms is not sufficient to be used for warfarin screening in Turkish patients.

Experimental model of hyperfibrinolysis designed for rotational thromboelastometry in children with congenital heart disease.

We assessed an in-vitro model of hyperfibrinolysis using rotational thromboelastometry (ROTEM) by the addition of increasing concentrations of tissue-type plasminogen activator (t-PA) on whole blood obtained from children undergoing cardiac surgery. We assessed the relevance of this model by repeating the tests in the same population after tranexamic acid (TXA) infusion. In addition, we determined the sensitivity and specificity of ROTEM parameters to detect the different degrees of fibrinolysis. Blood samples obtained from 20 children were analyzed at two predefined timepoints: after induction of anesthesia, before TXA (baseline), and at the end of surgery during TXA infusion (end surgery). At baseline, an extrinsic activation with tissue factor (EXTEM) test was performed without and with increasing concentration of t-PA (102, 255, 512, 1024, 1535, and 2539 units t-PA/ml). At the end of surgery, a second EXTEM test was performed without and with two different t-PA concentrations (1535 and 2539 units t-PA/ml). At baseline, increasing t-PA concentrations in the EXTEM test induced a gradual increase of hyperfibrinolysis characterized by a reduction in clot firmness and stability parameters. In the presence of TXA, t-PA-induced hyperfibrinolysis was completely abolished. Lysis-onset time (LOT) and degree of fibrinolysis measured at 30 min (LI30) best assessed the degree of fibrinolysis. This in-vitro model of t-PA-induced hyperfibrinolysis using the EXTEM test of ROTEM may represent a promising tool to assess hyperfibrinolysis in the pediatric population. In addition, we observed that LOT and LI30 should be considered as the best parameters to detect different degrees of fibrinolysis.

Effective reversal of edoxaban-associated bleeding with four-factor prothrombin complex concentrate in a rabbit model of acute hemorrhage.

BACKGROUND: Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor prothrombin complex concentrate (Beriplex/Kcentra; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model. METHODS: The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 µg/kg) + saline, or edoxaban (1,200 µg/kg) + four-factor prothrombin complex concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing. RESULTS: Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor prothrombin complex concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters. CONCLUSION: In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.

[Safe dose rTPA for massive pulmonary embolism associated with high bleeding risk: a case report and review of the literature]. / Utilizzo di safe dose di rTPA nel trattamento dell'embolia polmonare massiva associata ad elevato rischio emorragico: caso clinico e revisione della letteratura.

Systemic thrombolysis is a well known treatment for massive pulmonary embolism (PE) but it remains often underutilized in clinical practice because of the risk of major bleeding, especially intracranial hemorrhage. Recently, the use of safe-dose recombinant tissue-type plasminogen activator (rTPA) has been proposed for the treatment of moderate PE demonstrating to be safe and more effective than standard anticoagulation. We report the case of an 83-year-old male patient affected by massive PE associated with high bleeding risk, and treated with half-dose of rTPA that resulted in rapid clinical improvement. This clinical experience led us to focus on the role of reduced doses of rTPA to decrease bleeding risk in patients with PE. We conclude that the new concept of "safe-dose thrombolysis" with rTPA may be considered a reasonable and interesting option in high-bleeding risk patients with massive PE.

Tranexamic acid without prophylactic factor replacement for prevention of bleeding in hereditary bleeding disorder patients undergoing endoscopy: a pilot study.

The risk of bleeding in patients with hereditary bleeding disorders (HBD) undergoing gastro-intestinal (GI) endoscopic procedures is unknown but guidelines generally recommend correction of factor deficiency. Investigate the safety of oral tranexamic acid (TA) without prophylactic factor replacement to prevent bleeding complications in patients with HBD undergoing elective GI endoscopic procedures. A prospective single-arm pilot study testing the feasibility of using TA, without prophylactic factor replacement or desmopressin preprocedure, for prevention of bleeding complications following elective standard risk (<1% risk of bleeding) endoscopic procedures in patients with HBD. Baseline factor levels, haemoglobin and iron studies (IS) were measured preprocedure. Primary outcome of bleeding (NCI CTCAE v3.0 Bleeding Scale) was undertaken by patient review and repeat Hb, IS on day 21. Twenty-eight patients underwent 32 GI endoscopic procedures from September 2010 until June 2012. The median age was 53 years (range 24-75 years) and disease types included mild haemophilia A/B (n = 12), severe haemophilia A/B (n = 9), von Willebrand disease (n = 5), FXI deficiency (n = 1) and FVII deficiency (n = 1). Procedures performed included 11 gastroscopies, 12 colonoscopies, 8 gastroscopies and colonoscopies and 1 flexible sigmoidoscopy. Fourteen standard risk procedures and two high risk procedures were performed. Two patients experienced Grade 1 bleeding and one patient experienced Grade 2 bleeding. This study suggests that TA without prophylactic factor replacement may be a safe approach for mild and moderate HBD patients undergoing standard risk endoscopic procedures, particularly where no biopsy is performed. These findings should be confirmed in a larger study.

WFH: closing the global gap--achieving optimal care.

For 50 years, the World Federation of Hemophilia (WFH) has been working globally to close the gap in care and to achieve Treatment for All patients, men and women, with haemophilia and other inherited bleeding disorders, regardless of where they might live. The WFH estimates that more than one in 1000 men and women has a bleeding disorder equating to 6,900,000 worldwide. To close the gap in care between developed and developing nations a continued focus on the successful strategies deployed heretofore will be required. However, in response to the rapid advances in treatment and emerging therapeutic advances on the horizon it will also require fresh approaches and renewed strategic thinking. It is difficult to predict what each therapeutic advance on the horizon will mean for the future, but there is no doubt that we are in a golden age of research and development, which has the prospect of revolutionizing treatment once again. An improved understanding of "optimal" treatment is fundamental to the continued evolution of global care. The challenges of answering government and payer demands for evidence-based medicine, and cost justification for the introduction and enhancement of treatment, are ever-present and growing. To sustain and improve care it is critical to build the body of outcome data for individual patients, within haemophilia treatment centers (HTCs), nationally, regionally and globally. Emerging therapeutic advances (longer half-life therapies and gene transfer) should not be justified or brought to market based only on the notion that they will be economically more affordable, although that may be the case, but rather more importantly that they will be therapeutically more advantageous. Improvements in treatment adherence, reductions in bleeding frequency (including microhemorrhages), better management of trough levels, and improved health outcomes (including quality of life) should be the foremost considerations. As part of a new WFH strategic plan (2012-2014) the WFH has identified several key initiatives for particular emphasis - continuation of the Global Alliance for Progress (GAP) program, a new initiative to address underserved countries and regions (The Cornerstone Initiative), enhancing health outcomes research and analysis, and a new research mentorship program. Despite our progress to date in closing the global gap in care, our work is not complete. Too many patients remain undiagnosed and too few receive adequate treatment. This paper will also discuss historical, present and future challenges and opportunities to close the gap in care and achieve Treatment for All.

Pruebas del coagulograma y componentes de la hemostasia. Utilidad para diagnosticar las diátesis hemorrágicas / Tests of coagulation and hemostasis components. Usefulness for diagnosing hemorrhagic diathesis

El coagulograma comprende un conjunto de pruebas que exploran la participación de todos los componentes de la hemostasia: endotelio vascular, actividad plaquetaria, factores plasmáticos y fibrinolíticos. Con frecuencia, la ejecución de estas pruebas resulta compleja para el personal técnico, por lo que la profundización en el conocimiento e interpretación de los resultados de cada una de estas, debe redundar en el fortalecimiento y preparación de los profesionales de la salud. En el presente trabajo se describen las principales pruebas del coagulograma convencional, el principio y los valores de referencia de cada una, así como las posibles enfermedades de acuerdo con la alteración del sistema hemostático que corresponde a la alteración del coagulograma, con el objetivo de brindarle al médico una información básica para la correcta ejecución y adecuada interpretación de los resultados

Coagulogram comprises a set of tests, which explore the participation of all components of hemostasia: vascular endothelium, platelet activity, plasma and fibrinolytic factors. Often, the technical staff finds complex to do these tests, so deepening knowledge, understanding, and interpreting the results of each of these tests should result in strengthening and training of health professionals. This paper describes the main conventional coagulation tests, the beginning and the reference values of each of them, and the possible diseases according to the alteration of the hemostatic system corresponding to the alteration of coagulation, with the aim of providing medical background information for the proper performance and proper interpretation of results

Complications in oral and maxillofacial surgery: management of hemostasis and bleeding disorders in surgical procedures.

Oral and maxillofacial surgeons perform a wide variety of surgical procedures. One of the major complications of these various surgical techniques is uncontrolled bleeding. The best management of perioperative hemorrhage is prevention. This includes proper preoperative patient evaluation, knowledge of the various bleeding disorders, and the characterization of the correct methods of management. This article evaluates various causes of bleeding, and identifies both local and systemic and pathways. Considerations of treatment for patients with these various disorders are discussed regarding the best management options for adequate hemostasis.

Prophylaxis in bleeding disorders.

Primary prophylaxis with coagulation factor concentrates has become the standard of care for children with hemophilia to reduce the risk of bleeding and related morbidity. However, several important questions remain unanswered regarding the optimal use of prophylaxis in patients with bleeding disorders. Limited data are available on the use of primary prophylaxis in adults with hemophilia, although tailoring the dose and schedule of prophylaxis in adults based on the clinical course of the disease may improve convenience and reduce costs without compromising efficacy. Patients with severe forms of von Willebrand disease (VWD) are at risk of serious bleeding episodes and may therefore benefit from prophylaxis; results from ongoing trials, such as the VWD International Prophylaxis (VIP) trial, are expected to provide more insight into the efficacy and safety of prophylaxis in these patients. For patients with other rare bleeding disorders, prophylaxis may be considered, depending on the clinical course of the disease and the availability of factor replacement therapy products; definitive recommendations, however, are not possible given the lack of comprehensive studies evaluating prophylaxis in this setting. Ongoing studies will help further define the role of coagulation factor concentrate prophylaxis in patients with bleeding disorders.

Anesthetic implications for the patient with osteogenesis imperfecta.

Osteogenesis imperfecta is an inherited disorder of the connective tissue stemming from gross abnormalities in collagen formation and structure. Affected patients fall into 4 classifications each displaying the similar properties of easily fractured bones, hypermobile joints, blue or gray sclera, skeletal deformities, and fragile skin. More severe forms of the disease may manifest platelet dysfunction, cardiac anomalies, hypermetabolic syndromes, respiratory compromise, and/or basilar invagination. Treatment of osteogenesis imperfecta is mainly supportive, consisting of prompt surgical treatment of fractures to prevent deformity and maintaining mobility to lessen the chance of pulmonary or cardiovascular complications. These treatment modalities make anesthesia of paramount importance. Current literature exposes many potential anesthetic complications associated with osteogenesis imperfecta. The research shows that implications range from simply positioning the patient on the operating room table to management of rare occurrences such as malignant hyperthermia and basilar invagination. Commonly encountered complications include a difficult airway, intraoperative bleeding due to platelet dysfunction, respiratory compromise due to skeletal deformity, and congenital cardiac anomalies. Proper preparation and preoperative assessment is important, as is the choice of anesthetic technique. Correct identification of risk factors and optimization of health before surgery should lead to an uneventful anesthetic course.

Acute leukemia in women.

The treatment and survival outcome of acute leukemia in women is generally similar to that of men. However, acute leukemia in women poses additional challenges in clinical practice. In addition to important precautions during therapy, such as prevention of abnormal uterine bleeding in premenopausal women and therapy during pregnancy, women who are survivors of acute leukemia face unique and potentially long-term health-related problems. In this review, we address the aforementioned issues, as well as the various health and psychosocial challenges faced by women who survive childhood leukemia during their path to adulthood. Finally, we address the issue of therapy-related acute leukemia in the category of women who are survivors of breast and ovarian cancer.

Uso de desmopresina durante el embarazo en enfermedad de Von Willebrand / Desmopressin use during pregnancy in Von Willebrand diseases

La enfermedad de Von Willebrand es el desorden hemorragíparo más frecuente. Las mujeres constituyen una población particularmente sintomática debido al desafío hemostático de las menstruaciones y el parto. Nosotros revisamos las historias médicas de 54 mujeres con niveles disminuidos de factor von Willebrand (VWF) e historia de sangrado, quienes hubieran usado desmopresina durante el embarazo. No se observaron efectos adversos ni en las mujeres ni en los recién nacidos, incluso en los 5 expuestos a la medicación en el primer trimestre de gestación. No se observaron complicaciones locales asociadas a la colocación del catéter epidural. La DDAVP fue efectiva para prevenir el sangrado posparto. La desmopresina merece ser considerada como la primera elección de tratamiento; en aquellas pacientes con bajo niveles de VWF presentan complicaciones hemorrágicas, incluyendo mujeres embarazadas. Aunque el sangrado posparto aparece en una pequeña proporción de mujeres con VWD, no hay un modo apropiado de identificar quiénes van a sangrar. El uso de profilaxis con DDAVP debería ser tenido en cuenta como una alternativa segura y efectiva.

The von Willebrand disease (VWD) is the most frequent hemorrhagic disorder. Women with VWD are more symptomatic than men because the challenged of menses and delivery. We reviewed the records of 54 women with a low plasmatic VWF level and bleeding history, who had used desmopressin during pregnancy. No adverse effects were observed in mothers or newborns, incluiding those exposed to the drug during the first trimester. No local complication of epidural placement was observed. DDAVP was effective to prevent post-partum hemorrhage. DDAVP merits to be considered as the first choice of therapy, when patients with a previous or current low plasmatic VWF level present bleeding complications, including pregnant women. Although post-partum bleeding will appear in a small proportion of VWD women, there is no accurate way to identify who is going to bleed. The use of DDAVP should be regarded as a highly valuable option.