Primary Prophylaxis Of Bleeding Research Articles

Athn Transcends Natural History Cohort Study of Bleeding Symptoms and Treatment Outcomes in Patients with Glanzmann Thrombasthenia

Background Glanzmann thrombasthenia (GT) is a rare, inherited, qualitative platelet disorder caused by a deficiency of one or both platelet surface proteins alpha IIb beta 3. This protein on the platelet functions as the fibrinogen receptor and is essential for hemostasis. Individuals with GT have lifelong bleeding episodes that can be frequent and severe often involving the muco-cutaneous membranes. GT is an autosomal recessive disorder with variations of the ITGA2B or ITGB3 genes. The prevalence of GT is estimated to be 1:1,000,000 in the general population. In populations with high consanguinity, the prevalence is higher. Reports of the impact of living with GT are lacking. Platelets have previously been the mainstay of treatment for severe bleeding and to manage surgical bleeding in people with GT. However, platelet transfusions carry a number of risks including allergic reactions (anaphylaxis, acute lung injury), pathogen transmission, and the formation of allo-antibodies. Primary bleeding prophylaxis is currently not available and all treatment for bleeding is reactive and on-demand. As potential new therapies emerge, clinicians require unbiased, long-term data on the safety and effectiveness of both current and new therapies. Therefore, we designed a registry of people with GT with the aims of assessing the bleeding rate and phenotype for people with this condition, as well as describing their lived experience. Rationale Due to the rare nature of GT, data within individual center registries are naturally limited. There is variation in the data held and method of collection. The aim of the study is to collect biospecimens, phenotypic characteristics, bleeding patterns, and treatment utilization, from people who have been diagnosed with GT. To achieve this, a comprehensive, multi-institutional, observational cohort study will be conducted to: Allow collection of longitudinal safety and clinical practice data for treatments in patients with GT, allowing monitoring of recently approved and well-established therapies; Aid new discovery, through the collection of biospecimens and phenotype data; Provide sufficient, unified data capture in participants with this rare disorder across the United States. Objectives To describe the bleeding phenotype in GT, including the frequency of bleeds, the Site of bleeds, and to describe real-world effectiveness of therapies used in GT, by evaluating; the frequency of bleeds, Patient reported outcomes, Healthcare and treatment utilization, To create a database for future research. Methods ATHN Transcends (NCT04398628) assesses the safety and effectiveness of contemporary therapies for people with inherited bleeding and clotting disorders. The primary aim of ATHN Transcends is to collect specific adverse events harmonized with the European Haemophilia Safety Surveillance (EUHASS). The study is constructed to allow the addition of specific modules. We have designed the GT module in ATHN Transcends to assess the safety and effectiveness of current therapy for GT. In addition, we will be collecting data around the actual bleeding rate in those who live with GT as well as more fully describing the lived experience of being impacted by GT. The study will be conducted through ATHN-affiliated centers who care for those impacted by GT. Study Design This study is a longitudinal, natural history, observational cohort study of approximately 50 participants with GT at 16 ATHN-affiliated treatment centers across the United States and a sub-cohort from one international ATHN Affiliate. The minimum planned duration of study participation for participants is approximately 18 months. Up to 10 pediatric subjects aged 2 years to <10 years, up to 10 aged 10 to <18 years, and a minimum of 30 adults >18 years with GT are expected to be enrolled. Each subject will complete a daily record for three months of bleeding event details, and any treatments. Summary ATHN Transcends has received central IRB approval and is currently being rolled out across participating American Thrombosis and Hemostasis Network (ATHN) Affiliates in the United States. Enrollment in the GT Module can begin as soon as a site opens ATHN Transcends to enrollment. Conclusion ATHN Transcends provides a real-world mechanism in which to collect safety and effectiveness data of contemporary therapies for people with GT. The GT Module of ATHN Transcends will allow collection of Good Clinical Practice-grade data.

A Model for Early Endoscopic Detection of High-Risk Gastroesophageal Varices in Children With Biliary Atresia.

In children with biliary atresia and portal hypertension, progression to gastroesophageal varices carrying a risk of bleeding depends on age, total serum bilirubin concentration and initial endoscopic features. We report an attempt to use these factors for early detection of high-risk varices (HRVs). Based on different combinations of these factors, a model was set to estimate the probabilities of emergence of HRVs at various time intervals. A 10% probability was chosen to set the date of the next endoscopy in children who did not display HRVs initially. A total of 113 children without HRVs who underwent their first endoscopy before age 8 in 2013-2020 were included. A comparison was made with children seen during the period 1990-2012 when this model was not used. In all, 65 of the 113 children underwent one to five additional endoscopies at dates set according to the model. The emergence of HRVs was recorded in 22 children after a mean interval of 14 months and was managed by endoscopic primary prophylaxis in all but one who underwent liver transplantation. Three other children bled before the next planned endoscopy. Compared with 175 children of the same age ranges without HRVs in the period 1990-2012, the use of the model was associated with a faster detection of HRVs with a lower number of endoscopic procedures (P = 0.0022 and P = 0.023, respectively). The results suggest that the model reported may be a useful tool for the early detection of HRVs to allow primary prophylaxis of bleeding.

Long-term outcome of endoscopic variceal band ligation of esophageal varices in patients with chronic liver disease.

There are scanty data on the long-term outcome of endoscopic variceal band ligation (EVL) for esophageal varices. Adult patients suffering from a chronic liver disease (CLD) undergoing EVL of esophageal varices of grade 2 and above between January 2006 andDecember 2015 were followed upfor the recurrence of varices, worsening of portal hypertensive gastropathy (PHG), rebleeding, and mortality. EVL was done as primary prophylaxis of bleeding in 72 and as secondary prophylaxis in 175 patients. All received propranolol after EVL if there was no contraindication. Two hundred and forty-seven CLD patients (mean age 51.83 ± 11.28years, 179 males) underwent 306 EVL sessions. The most common etiology was alcohol (53%). Sixty-eight percent of patients had grade 3 esophageal varices 76.5%had PHG. There was no immediate post-EVL bleeding or 30-day mortality. Variceal obliteration was achieved in 100% with 19% recurrence within amean period of53.74 ± 27.2months. PHG worsened in 49.7%. Overall, rebleeding occurred in 13.8%, 4.3% from recurrent varices. There was no difference in variceal recurrence (16.7% vs. 20%) and incidence of rebleeding (9.7% vs. 13.7%) between patients undergoing EVL for primary and secondary prophylaxis. Cumulative rebleeding rates after 1, 5, and 9years were 1.6%, 9.2%, and 11.4%, respectively. The overall mortality was 85%, mostly from progressive CLD, and only 8.6% was due to rebleeding. On subgroup analysis, the factors significantly associated with rebleeding was Child-Pugh class C and worsened PHG those with mortality were alcohol and Child-Pugh class C. EVL is effective in the long-term for both primary and secondary prophylaxis of esophageal variceal bleeding.

Principles of primary prophylaxis of bleeding from oesophagealvaricies in patients with liver cirrhosis

The principles of primary prevention of bleeding from esophageal varices in patients with liver cirrhosis are discussed with reference to the stage ofportal hypertension. The information was collectedfrom the PubMed database, Google Scholar retrieval system, Cochrane reviews, and lists of references from relevant publications for 1980-2015 using the key words «bleeding from esophageal varices», «prophylaxis», «portal hypertension». Inclusion criteria were confined to primary prophylaxis of bleeding from esophageal varices in patients with liver cirrhosis. The analysis showed that the drugs of choice for primary prophylaxis of bleeding from esophageal varices in patients with liver cirrhosis are non-selective beta-adrenoblockers, but their application is indicated only in case of clinicallyl significant portal hypertension in patients with large and mediumsize esophageal varices. When the use of these drugs is contraindicated, endoscopic ligation of esophageal varices can be recommended.

Improving survival of cirrhosis patients with hepatocellular carcinoma through application of standard of care

We read with great interest the article by Ripoll et al.1 recently published in Hepatology. In their study the authors observed that prophylaxis of rebleeding from esophageal varices in cirrhosis patients with hepatocellular carcinoma (HCC) is associated with improved outcome. Furthermore, confirming previous findings, they observed that patients with HCC who bled had a worse outcome as compared to a matched group of bleeding cirrhosis patients without liver cancer.1-3 One of the most interesting results of this study, however, was that fewer patients with HCC received secondary prophylaxis after bleeding, and that lack of secondary prophylaxis was an independent predictor of death. We feel that this study touches upon an important issue in the management of cirrhosis patients, and more so in cirrhosis patients with HCC. In fact, despite recent evidence of improved outcome, the mortality rate associated with variceal bleeding is still as high as 20%.4, 5 Furthermore, although primary prophylaxis of variceal hemorrhage may be associated with an overall benefit that goes beyond a simple decrease in bleeding rate, and the unavailability of accurate noninvasive methods able to obviate the need for endoscopy, the proportion of patients at risk of bleeding who actually undergo screening endoscopy is low.6-9 Moreover, the proportion of patients who, after a positive screening result, actually undergo primary prophylaxis is unknown. Noteworthy, the study by Ripoll et al.1 shows that less than half (43%) of eligible patients with cirrhosis and HCC were on primary prophylaxis of bleeding. This finding is clinically meaningful, as we have previously shown that in patients with HCC the presence of varices is independently associated with death, and death due to bleeding is significantly more frequent in patients with varices.10 However, due to insufficient data our study was not able to identify whether the presence of varices simply identified patients with more advanced disease—and therefore at higher risk of bleeding and death—and which was the proportion of patients on bleeding prophylaxis. In this regard, the study by Ripoll et al. shows us that cirrhosis patients with HCC who bled received a suboptimal management, and puts forward the hypothesis that this may be due to the perception that intensive management would not result in a meaningful clinical benefit when HCC is present. Instead, their results clearly show that lack of rebleeding prophylaxis is associated with increased mortality, even after adjustment for the severity of liver disease. This information calls us to a more thorough management of these patients. All in all, we feel that studies like this are extremely useful for clinical practice, providing data that should remind us that some measures, such as primary and secondary prophylaxis of variceal bleeding, are standard of care and not options in the management of cirrhosis patients, regardless of the presence of HCC. Edoardo G. Giannini, M.D., Ph.D.1 Franco Trevisani, M.D.2 1Dipartimento di Medicina Interna Unità di Gastroenterologia IRCCS Azienda Ospedaliera Universitaria San Martino IST Università di Genova Genova, Italy 2Dipartimento di Scienze Mediche Chirurgiche Unità di Semeiotica Medica, Alma Mater Studiorum Università di Bologna Bologna, Italy

Endoscopic variceal band ligation compared with propranolol for prophylaxis of first variceal bleeding

Administration of nonselective beta-blockers in prophylaxis of first variceal bleeding is not suitable for all patients. Thus, we evaluated endoscopic variceal band ligation (EVBL) in primary prevention of bleeding in patients with cirrhosis and large esophageal varices. A total of 73 consecutive patients with liver cirrhosis and large esophageal varices without a history of gastrointestinal bleeding were randomized to receive either EVBL or propranolol and were followed for up to 18 months. Forty patients underwent EVBL and 33 patients received propranolol. Variceal bleeding occurred in 2 patients in the EVBL (5%) and in 2 patients in the propranolol group (6%, NS). The 18 month actuarial risk for first variceal bleed was 5% in the EVBL (95% CI, 0-12%) and 20% in the propranolol group (95% CI, 0-49%, NS). The actuarial probability of death at 18 months of follow-up was 5% (95% CI, 0-11%) in the EVBL group and 7% (95% CI, 0-17%, NS) in the propranolol arm. In conclusion, EVBL was an effective and safe alternative to propranolol in primary prophylaxis of bleeding in patients with large esophageal varices.

Variceal Bleeding: Prophylaxis, Treatment, and Prevention

Variceal bleeding leads to significant morbidity and mortality in patients with portal hypertension. Mortality can be greater than 50% with the initial bleed and many patients develop recurrent bleeding with equal or greater mortality. Currently cirrhosis is the leading cause of portal hypertension, which is defined as a hepatic vein-portal vein gradient greater than 5 mmHg. Portal hypertension may arise from increased splanchnic blood flow due to systemic vasodilation that occurs in the hyperdynamic circulation of cirrhosis or from increased vascular resistance in intrahepatic and/or portocollateral vessels; by decreasing splanchnic blood flow, portal inflow decreases and so does portal pressure. Pharmacologic therapy consisting of nonselective β-blockers, vasopressin, and octreotide act by decreasing splanchnic blood flow, and long-acting nitrates may cause direct vasodilation of portocollateral vessels and/or decreased splanchnic blood flow. Nonselective β-blockers are the cornerstone of treatment for primary prophylaxis of bleeding, whereas vasopressin and octreotide are used for acute hemorrhaging. Two endoscopic modalities are available for control of acute bleeding and prevention of recurrent bleeding: sclerotherapy and endoscopic variceal ligation. After standard airway control and adequate fluid resuscitation, endoscopy helps localize the area of bleeding, and often in conjunction with vasopressin or octreotide can help control bleeding. Empiric antibiotics (fluoroquinolones or third-generation cephalosporins) should be started prior to endoscopy and early in the course of treatment. Sclerotherapy and band ligation along with nonselective β-blockers can help prevent recurrences of bleeding. For patients with bleeding gastric varices or uncontrollably bleeding esophageal varices, interventional radiologic procedures such as the transjugular intrahepatic portosystemic shunt (TIPS) can be used, and depending on the clinical condition and Child's classification of the patient, a surgically created portosystemic shunt may be appropriate treatment. Hopefully with emerging, new techniques and more widespread, prudent use of prophylactic drugs and endoscopy, the mortality and morbidity of variceal bleeding can be reduced.

The use of endoscopic band ligation for the prophylaxis of variceal haemorrhage

The use of endoscopic band ligation for the prophylaxis of variceal haemorrhage

Prophylactic Therapy for Variceal Hemorrhage Revisited

The high mortality of a first variceal bleed in cirrhotic patients even in very recent studies makes some effective form of primary prophylaxis desirable. Controlled studies of shunt and nonshunting surgery have shown that these operations can prevent variceal hemorrhage only at the expense of increased morbidity and mortality. Therefore, this type of surgery has no place in the primary prophylaxis of variceal bleeding. Liver transplantation, however, is becoming a real therapeutic alternative for many patients with chronic liver disease. Obviously, it will prevent bleeding in many patients, but primary prophylaxis of bleeding itself is not an indication for a transplant. The radically different results of randomized controlled trials of prophylactic sclerotherapy indicate that it is either very helpful and will save many lives or very harmful and will lead to death in patients who would otherwise survive. The cumulative evidence from the trials that took appropriate care of effective treatment for the acute bleed and that had no major problems with complications of the procedure itself suggests that prophylactic sclerotherapy is neither helpful nor very harmful. Thus, there is also no indication for prophylactic sclerotherapy in clinical routine. Personally, I even doubt that it should be used in future controlled trials in the light of the positive results of the prophylactic trials of beta-blockers. If there is an indication for prophylactic treatment, it should be the last invasive treatment available. In the near future, work should focus on the confirmation and further development of endoscopic or other simple and safe means to predict the risk of first bleeding; on the development and characterization of effective drugs; and on development of methods to identify at an early stage responders and nonresponders. If I presently had large varices that had not yet bled, I would like to join one of my senior colleagues and look for admission to the Control group of an ongoing randomized beta-blocker trial.