Clinical Evidence Of Bleeding Research Articles

Prognostic implication of hemoglobin reduction with and without clinical bleeding after percutaneous coronary intervention in patients with acute coronary syndromes.

Bleeding events are associated with higher mortality rates in patients with cardiovascular diseases, including patients presenting with acute coronary syndrome (ACS) undergoing coronary revascularization. We aimed to determine whether a reduction in hemoglobin (Hgb) from pre- to postpercutaneous coronary intervention (PCI), with or without evidence of clinical bleeding, is a correlate of in-hospital mortality for patients presenting with ACS who underwent primary PCI. We divided 33816 consecutive patients with ACS who underwent PCI into threecategories: (1) target group (defined as Hgb reduction without overt bleeding [n = 112]); (2) Hgb reduction with overt bleeding (n = 48); and (3) control group (defined as no Hgb reduction and no overt bleeding [n = 3156]). Hgb reduction was defined as a drop of >3 g/dLin Hgb value from preprocedure and postprocedure during the index hospitalization. The primary outcome was in-hospital mortality. We used logistic regression to examine the relationship between Hgb reduction with and without bleeding and in-hospital mortality. In crude analysis, the Hgb reduction with overt bleed group had a higher in-hospital mortality rate (16.7%) than the target (9.8%) and control groups (0.6%). Adjusted logistic regression estimates a 0.393 (95% confidence interval [CI]: 0.137, 1.869) odds ratio for in-hospital death of the target group over the Hgb reduction with bleed group, and a 54.517 (95% CI: 2.07, >1000) odds ratio of the target group over the control group. In patients presenting with ACS undergoing PCI, Hgb reduction with and without overt bleeding were both independently associated with in-hospital mortality.

Evaluation of a Hydrogel Liquid Embolic Agent in a Porcine Mesenteric Hemorrhage Model

PurposeTo evaluate the ability to achieve hemostasis of a new liquid embolic agent in a porcine mesenteric artery hemorrhage model. Materials and MethodsAn anticoagulated porcine mesenteric artery hemorrhage model was created using a transarterial approach. Arterial hemorrhage was the result of aspiration needle punctures and simultaneous radiofrequency current application. Ten injured mesenteric arteries in 8 swine were treated. The hydrogel liquid embolic agent under investigation, an aqueous-based and in situ polymerizing liquid embolic agent, was used to treat actively bleeding sites. At 7 days, confirmation angiography was performed, followed by necropsy. ResultsThe mesenteric arterial injuries produced persistent and angiographically visible hemorrhage before initiating embolic therapy. Arteriovenous fistulae were observed in 4 cases. Embolization led to hemostasis in 10 of the 10 bleeds (100%). The mean embolic agent delivery time was 5.3 minutes (range, 1–15 minutes) with a mean embolic agent volume of 2.9 mL (range, 0.8–5.2 mL) delivered to achieve hemostasis. Notably, 40% of the treatments embolized the injury in the artery at the treatment site while leaving the native arterial lumen patent for the 7-day term of survival. All animals survived with no clinical evidence of hemorrhage through 7 days. Necropsy did not reveal evidence of ischemia within the bowel, liver, or lung. ConclusionsA new hydrogel liquid embolic agent was found to achieve rapid and durable hemostasis in an animal model of acute mesenteric hemorrhage.

Is Bone Grafting during Implant Placement a Protective Factor against the Development of Peri-implantitis? A Retrospective Cohort Analysis

This study aims to identify if the use of bone grafting at time of implant placement is a protective factor against the development of peri-implantitis. A retrospective cohort study was conducted at the Philadelphia Veterans Affairs Medical Center from 2006 to 2013. Physician encounter notes within three months of implant placement were used to gather data about patients' health status. Operative report notes were used to assess the use of bone grafting at time of implant placement. Implant status was assessed using dental encounter notes and radiographs from follow-up appointments at one, three, five and 10 years. Peri-implantitis was defined as radiographic evidence of changes in the crestal bone level, clinical evidence of bleeding on probing with or without suppuration. Electronic medical records of 797 implants were retrospectively analyzed. Statistics were computed using the SAS System (SAS Institute Version 9.4, 2002-12, Cary, NC). The primary predictor variable was bone grafting at time of implant placement (xenograft, allograft or autograft). The primary outcome variable was the presence of peri-implantitis. Other study variables assessed were diabetes, smoking, gender and age. Descriptive, univariate and multivariate regression analyses were performed to measure the association between predictive variables and development of peri-implantitis. Of the 797 implants placed, 168 (21%) developed peri-implantitis. Following a multivariate analysis that controlled for diabetes, smoking, gender and age, placement of bone graft at implant placement was shown to be associated with a decreased risk in the presence of peri-implantitis (p = 0.050) when compared to implants that did not receive bone graft. The data from this study show that implants placed with simultaneous bone graft were 44.7 percent less likely to develop peri-implantitis compared to implants placed without bone graft (OR = 0.553, 95 percent Cl 0.303-1.000). To the researchers' knowledge, no existing literature demonstrates this significant, protective relationship. Human studies demonstrate a significant contraction of ridge dimensions following extraction, even when immediately restoring with an implant. However, the placement of bone graft during implant placement was shown to histologically modify the process of bone healing and provide additional hard tissue at the extraction socket when compared to sockets restored with no graft. Therefore, in conjunction with the results, the use of bone graft at the time of implant placement may reinforce the surrounding implant site on a biochemical or structural level and provide protective features against the development of peri-implantitis. Analysis of implants placed at the Philadelphia VA Medical Center revealed an important association between use of bone grafting at implant placement and the development of peri-implantitis. The study shows that the supplemental placement of bone graft may play a role in decreasing the development of peri-implantitis. However, it is important to note that the use of bone grafting is case-specific for areas that may be deficient of peri-implant tissue. As the restoration of edentulous areas with dental implants is becoming the new standard of care, identifying protective factors, such as use of bone grafting during implant placement, will be critical in ensuring successful outcomes. In addition to completing prospective studies, identification of other implant protective and risk factors is a necessity. 1. Lang, NP, et. al: Periimplant diseases: where are we now? consensus of the Seventh European Workshop on Periodontology. J Clin Periodontol, 2011. 2. Alves D, Faria-Almeida R, Azevedo A, Liñares A, Muñoz F, Blanco-Carrion J: Immediate 1-piece zirconia implants with/without xenograft in the buccal gap: a 6-month pre-clinical study. Clin Oral Implants Res, 2021

Is Immunosuppression a Risk Factor for Development of Peri-implantitis? A Retrospective Cohort Analysis

The present study aims to identify if immunosuppression is a risk factor for the development of peri-implantitis. A retrospective cohort study design was conducted on patients presenting to the Philadelphia Veterans Affairs (VA) Medical Center for dental implant placement from 2006 to 2013. Medical encounter notes within 3 months of implant placement were used to collect information about patients’ health status, including evaluations of immune system function. Implant status was assessed using dental encounter notes and radiographs from follow-up appointments at 1, 3, 5, and 10 years. Peri-implantitis was defined as radiographic evidence of change in crestal bone level, clinical evidence of bleeding on probing, with or without suppuration.1Electronic medical records of 884 implants were retrospectively analyzed. Descriptive statistics were calculated using the SAS System (SAS Institute Version 9.4, 2002-2012, Cary, NC). The primary predictor variable was immunosuppression. The primary outcome variable was the presence of peri-implantitis. Other study variables assessed included graft at the time of implant placement, diabetes, smoking, gender, and age over 60. Descriptive, univariate, and multivariate regression analyses were performed to measure the association between predictive variables and development of peri-implantitis.Of the 884 implants placed, 205 (23.1%) developed peri-implantitis. Following a multivariate analysis that controlled for diabetes, smoking, gender, and age over 60, immunosuppression was shown to be significantly associated with an increased risk in the presence of peri-implantitis (P = .0071) when compared to implants placed in immunocompetent subjects. The data from this study show that implants placed in immunosuppressed patients were 29.78% more likely to develop peri-implantitis compared to implants placed in immunocompetent patients (OR = 2.229, 95% CI 1.243-3.996). To the best of the authors’ knowledge, no existing literature has demonstrated this significant risk relationship.Following surgical implant placement, adequate function of the immune system's inflammatory response is imperative to target infections and orchestrates wound healing to allow for successful osseointegration of implants. Few studies, however, have directly investigated this nexus at a mechanistic level. In vivo studies in rabbits have indicated that titanium implant placement may up-regulate the immune system's type 2 inflammatory response to inhibit bone resorption markers and promote healing.2 Therefore, in conjunction with the authors' results, immunosuppression could play a significant role in increasing risk of peri-implantitis.Analysis of implants placed at the Philadelphia VA Medical Center revealed an important association between immunosuppression and the development of peri-implantitis. This study shows that immunosuppression may play a role in increasing the development of peri-implantitis. Along with need for further exploration regarding the pathophysiology of this relationship, additional observational and randomized controlled studies are necessary to validate the authors' findings. As implant restoration of edentulous areas is becoming the new standard of care, identification and understanding of associated risks factors are critical to ensure successful implant outcomes.

Acute visual deterioration and headaches in a patient with suprasellar lesion: Answer

•Cavernous malformation should be a differential diagnosis of suprasellar lesions.•Management of asymptomatic optic apparatus cavernous malformation is still debatable.•The relative risk of visual deterioration after repetitive hemorrhage may be higher than the risk of surgical removal. D. Optic tract cavernoma The patient underwent surgery through a left pterional craniotomy, and the intraoperative findings revealed a cavernoma in the left optic chiasm extending forward into the left optic nerve and posteriorly to the optic tract. (Fig. 3). Cavernous malformation (CM) is a common intracranial vascular lesion and accounts for 10 – 15% [1Tan T. Tee J.W. Trost N. McKelvie P. Wang Y.Y. Anterior visual pathway cavernous malformations.J Clin Neurosci. 2015; 22: 258-267Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 2Moriarity J.L. Clatterbuck R.E. Rigamonti D. The natural history of cavernous malformations.Neurosurg Clin N Am. 1999; 10: 411-417Abstract Full Text PDF PubMed Google Scholar] of the cases. The most common location is supratentorial (80%), brainstem (15%), and spinal cord (5%). Optic nerve CMs are very rare, with only 70 cases reported in the literature [3Voznyak O. Lytvynenko A. Maydannyk O. Kalenska O. Hryniv N. Cavernous Hemangioma of the Chiasm and Left Optic Nerve.Cureus. 2020; 12e8068PubMed Google Scholar, 4Hempelmann R.G. Mater E. Schröder F. Schön R. Complete resection of a cavernous haemangioma of the optic nerve, the chiasm, and the optic tract.Acta Neurochir (Wien). 2007; 149: 699-703Crossref PubMed Scopus (30) Google Scholar, 5Mano Y. Kumabe T. Saito R. Watanabe M. Tominaga T. Cavernous malformation of the optic pathway mimicking optic glioma: a case report.Childs Nerv Syst. 2014; 30: 1753-1758Crossref PubMed Scopus (7) Google Scholar, 6Hassler W. Zentner J. Wilhelm H. Cavernous angiomas of the anterior visual pathways.J Clin Neuroophthalmol. 1989; 9: 160-164PubMed Google Scholar]. The relative risk of hemorrhage from asymptomatic supratentorial cavernomas is 0.7 to 3.1% per year [[7]Liu J.K. Lu Y. Raslan A.M. Gultekin S.H. Delashaw J.B. Cavernous malformations of the optic pathway and hypothalamus: analysis of 65 cases in the literature.Neurosurg Focus. 2010; 29: E17https://doi.org/10.3171/2010.5.FOCUS10129Crossref PubMed Scopus (45) Google Scholar] Management of asymptomatic CM within the optic apparatus is problematic and requires consideration of the relative risk of hemorrhage with devastating visual loss consequences against those of surgery. In contrast, the risk increases in patients with previous hemorrhages up to 3.8% to 22.9% [[7]Liu J.K. Lu Y. Raslan A.M. Gultekin S.H. Delashaw J.B. Cavernous malformations of the optic pathway and hypothalamus: analysis of 65 cases in the literature.Neurosurg Focus. 2010; 29: E17https://doi.org/10.3171/2010.5.FOCUS10129Crossref PubMed Scopus (45) Google Scholar]. Since a small hemorrhage from a cavernoma located in the anterior optic apparatus could have catastrophic consequences, we recommend resection of the lesion in cases with radiological or clinical evidence of hemorrhage [[8]Crocker M. DeSouza R. King A. Connor S. Thomas N. Cavernous hemangioma of the optic chiasm: a surgical review.Skull Base. 2008; 18: 201-212Crossref PubMed Scopus (20) Google Scholar], as subsequent hemorrhage risk with visual loss is increased (Fig. 1, Fig. 2).Fig. 2A) Axial T1-weighted gadolinium-enhanced MRI, and B) axial T2-weighted MRI showing a left side non-enhancing hypointense suprasellar lesion, in a 62-year-old woman.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 3A) Intraoperative image of the left optic tract cavernoma removal (blue arrow) through a left pterional craniotomy, compressing the left optic nerve (red arrow) B) Intraoperative image after removal of the cavernoma, showing the left optic tract (blue star) and the optic chiasm (blue arrow head).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acute visual deterioration and headaches in a patient with suprasellar lesion: QuestionJournal of Clinical NeuroscienceVol. 86PreviewA 62-year-old woman presented with a history of headaches for two weeks and sudden loss of vision in her left eye. Neurological examination revealed right eye acuity 6/6, left eye 6/9.5, left eye relative afferent pupillary defect (RAPD), red desaturation reduced in the same eye, confrontation visual fields showed non-congruent right homonymous hemianopia. Fundoscopy did not show any sign of papilledema or chronic optic atrophy (Fig. 1). There was no other focal neurological deficit [1–8]. Full-Text PDF

Is Implant Placement in the Operating Room a Risk Factor for the Development of Peri-Implantitis? A Retrospective Cohort Analysis

This study aims to identify if preoperative antibiotic administration is a protective factor for the development of peri-implantitis in implants placed in the operating room vs outpatient clinic. A retrospective cohort study was conducted at the Philadelphia Veterans Affairs Medical Center from 2006 to 2013. Physician encounter notes within 3 months of implant placement were used to gather data about patients’ health status, including the setting of implant placement in the operating room vs outpatient clinic. Operative report notes were used to assess administration of antibiotic prophylaxis, recorded as none, oral, or intravenous administrations. Implant status was assessed using dental encounter notes and radiographs from follow-up appointments at 1, 3, 5, and 10 years. Peri-implantitis was defined as radiographic evidence of changes in the crestal bone level, clinical evidence of bleeding on probing, with or without suppuration.1 Electronic medical records of 942 implants placed in 398 unique patients were retrospectively analyzed. Descriptive statistics were computed using the SAS System (SAS Institute Version 9.4, 2002-2012, Cary, NC). Predictor variables were implant placement in the operating room or outpatient clinic and administration of preoperative antibiotics. The primary outcome variable was the presence of peri-implantitis. Descriptive, bivariate, and multiple logistic regression analyses were performed to measure the association between predictive variables and development of peri-implantitis. Of the 942 implants placed, 205 (22%) developed peri-implantitis. Overall, placement of implants in an operating room was shown to be associated with an increased risk in the presence of peri-implantitis (P ≤ .0001) when compared to implants placed in the outpatient clinic. When controlling for preoperative antibiotics, patients who received implants in the operating room were still found to be at risk for developing peri-implantitis (P = .0015). The data from this study show that implants placed in the operating room were 4 times more likely to develop peri-implantitis compared to implants placed in the outpatient clinic (OR = 4.056, 95% Cl 2.697-6.102). To our knowledge, no existing literature demonstrates this significant relationship. Our data show that preoperative antibiotics are protective against the development of peri-implantitis in patients who receive implants in the operating room. When controlling for preoperative antibiotics, operating room patients’ risk of developing peri-implantitis decreased by nearly 35% (OR = 2.633, 95% Cl 1.448-4.788). Studies have demonstrated that in a peri-implantitis model, antibiotic-treated specimens attenuated natural bone loss. The authors suggest that preoperative antibiotic administration may decrease the occurrence of peri-implantitis by reversing inflammatory responses and decreasing attachment loss via attenuation of pathogenic oral bacteria at the site of implant placement.2 Therefore, the administration of preoperative antibiotics, especially in medically complex patients who cannot tolerate implant placement in an outpatient clinic, may temper the progression of pathological processes around the peri-implant tissues. Analysis of implants placed at the Philadelphia VA Medical Center revealed an important association between the setting of implant placement, use of preoperative antibiotics, and the development of peri-implantitis. Our study shows that a standardized preoperative antibiotic regimen can play an important role in decreasing the development of peri-implantitis in patients who receive implants in an operating room. Administration of preoperative antibiotics in these patients may provide an opportunity to abate inflammatory reactions as a result of an existing complex disease and provide protection against the development of peri-implantitis. In addition to completing prospective studies, identification of other protective factors in this high-risk patient population is a necessity.

CUTANEOUS AND HEMORRHAGIC BLEEDING INJURIES OF THE IDIOPATHIC THROMBOCYTOPENIC PURPURA

The idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease of unknown cause being attributed by some authors as an immune response to some types of vaccine as a trigger of the disease. It is estimated that 10 in every 100,000 middle-aged individuals develop the disease. The first treatment choice is corticosteroids, and the diagnosis is performed with clinical evidence of bleeding, bruises, epistaxis, petechiae, and hematologic tests that confirm intense thrombocytopenia. This case report is about a melanoderma patient, 34 years old, who had a sudden appearance of bruising on various areas of the body and presence of petechiae and hemorrhagic blisters in the oral cavity. Hematologic examinations showed intense thrombocytopenia (30,000 platelets); the patient was treated with a corticosteroid and bevacizumab without adequate response and because it was a refractory disease, the patient underwent chemotherapy with vincristine leading to remission of the disease.

Transfusion Practice Following Intracranial Hemorrhage in Acute Leukemia: An Institutional Review

▪Background: Intracranial hemorrhage (ICH) is a common complication in acute leukemia that is associated with significant morbidity and mortality. While evidence supports prophylactic platelet transfusions at a threshold < 10 x 109/L to reduce the risk of bleeding in acute leukemia, there is little data to guide platelet transfusion practice in patients following ICH. The objectives of this study were to characterize the clinical features and outcomes of acute leukemia patients with ICH and to understand current platelet transfusion practice following ICH.Methods: This was a retrospective study conducted at a large, quaternary, academic cancer centre. We included all adult patients with a diagnosis of acute leukemia who had a documented ICH at our centre between January 1, 2009 and December 31, 2016. We assessed demographics, medications, infection and bleeding history in the week preceding ICH, characteristics of ICH including site of bleed, acute management, transfusion practice in the first 90 days, and clinical outcomes. Radiologic scans were re-assessed by neuroradiology to determine if the ICH was stable or if new or progressive bleeding had developed. Transfusion practice following the ICH was compared between the two groups with longitudinal data analysis using platelet counts as outcome. Kaplan-Meier product limit method was used to estimate overall survival (OS) rates as well as to obtain median survival; log-rank test was used to compare OS among those without new or progressive ICH vs. those with progression.Results: During the study period, of 2576 patients diagnosed with acute leukemia, 101 suffered from ICH and were included in the study. Most patients (94) had AML, of which 9 had APL, 6 had ALL, and 1 had MPAL. At the time of ICH, 61 patients were newly diagnosed or receiving induction chemotherapy, 33 had relapsed disease and 7 were in complete remission. Spontaneous ICH occurred in 76 patients. Within the week preceding ICH, 7 patients were on medications known to increase bleeding risk and 39 were on tranexamic acid. Sixty-four patients had clinical evidence of bleeding elsewhere and 22 had evidence of infection.On the day of ICH, the median platelet count was 16 x 109/L (range 0- 433 x109/L). Thirty-one patients had a platelet count < 10 x 109/L and 10 of these patients received a platelet transfusion prior to the bleed. Seventy patients had a platelet count ≥10 x109/L and 17 of these received a platelet transfusion prior to the bleed. Six patients (6%) exhibited evidence of platelet transfusion refractoriness.In the 90 days following ICH, 21% of platelet transfusions were given for a platelet count < 10 x 109/L, 55% were given with a platelet count between 10-29 x109/L, and 24% were given with a platelet count ≥ 30 x 109/L. New or progressive ICH occurred in 28 patients. The median platelet transfusion threshold was 19 x 109/L (range 0-114 x 109/L) for those without new or progressive ICH and 21 x 109/L (range 0-93 x 109/L) for those with progression (p=0.04; Figure 1). Of the 101 study patients, 79 have died. Median OS was 5.6 months for those without new or progressive ICH and 2.9 months for those with progression (p=0.002) (Figure 2). Cause of death was attributed to non-ICH causes in the majority of patients 65/79 (82%).Conclusions: In this retrospective study, we evaluated the outcomes of 101 patients with acute leukemia and ICH. At the time of the bleed, the majority of patients had active disease and more than two thirds had platelet counts of 10 x 109/L or higher. During 90 days of follow-up, nearly one third of patients developed new or progressive ICH. Platelet transfusion practice was variable and the median threshold was, in fact, higher in those who subsequently developed new or progressive bleeding. The reasons for this were unclear from our chart review, but we hypothesize that these patients may have had additional risk factors, e.g. fever, infection. The outcomes of patients with acute leukemia and ICH are poor. Factors other than platelet transfusion threshold likely contribute to secondary ICH events and the overall poor prognosis. DisclosuresMaze:Novartis: Consultancy, Honoraria.

Characteristics of hemostasis during experimental Ehrlichia canis infection.

Background Ehrlichia canis infection in dogs can cause thrombocytopenia and clinical evidence of bleeding. It is unknown why some dogs show signs of bleeding whereas others do not despite clinically relevant thrombocytopenia.Hypothesis/ObjectivesActivated platelets, decreased fibrinolysis or both mitigate bleeding tendency. Assess standard hemostatic variables, platelet dynamics, and specialized coagulation testing in dogs experimentally infected with E. canis to evaluate this clinical discrepancy.AnimalsFour healthy laboratory beagles.MethodsDogs were given blood infected with E. canis IV. Platelet indices of activation, platelet aggregometry, antiplatelet antibodies (percent IgG), complete coagulation panel, and thromboelastography (TEG) were measured before inoculation and on weeks 1‐8. Dogs were treated with doxycycline at approximately 5 mg/kg PO q12h between weeks 3 and 4 (day 24). For each variable, 1‐way repeated measures analysis (1‐way ANOVA) with post‐hoc analysis was performed with statistical significance set at P < .05.ResultsDogs had significantly lower platelet counts, evidence of activated platelets, and antiplatelet antibodies during E. canis infection. Dogs also appeared hypercoagulable and hypofibrinolytic using TEG as compared with baseline, changes that persisted for variable amounts of time after doxycycline administration. No overt signs of bleeding were noted during the study.Conclusions and Clinical ImportanceActivated platelets and a hypercoagulable, hypofibrinolytic state could explain the lack of a bleeding phenotype in some dogs despite clinically relevant thrombocytopenia. Findings from our pilot study indicate that additional studies are warranted.

How Low Is Too Low? Postpartum Hemorrhage Risk among Women with Thrombocytopenia.

Objective To estimate the association between severity of thrombocytopenia and postpartum hemorrhage. Study Design We performed a secondary analysis of a prospective cohort of women delivering by cesarean or vaginal birth after cesarean conducted by the National Institute of Child Health and Human Development (NICHD) Maternal–Fetal Medicine Unit. Women delivering ≥ 20 weeks with platelets &lt; 400,000/mL were included. Thrombocytopenia was defined as predelivery platelets of &lt; 150,000/mL. Primary outcomes were (1) laboratory evidence of hemorrhage, defined as a decrease in hemoglobin ≥ 4 mg/dL and (2) clinical evidence of hemorrhage, a composite of atony, transfusion, coagulopathy, hysterectomy, laparotomy, or intensive care unit admission. Odds ratios were calculated for primary outcomes using thrombocytopenia as a dichotomous and ordinal variable. Results A total of 54,597 women were included; 5,611 (10.3%) had antepartum thrombocytopenia, 1,976 (3.6%) women had laboratory evidence of hemorrhage, and 3,862 (7.1%) had clinical evidence of hemorrhage. Thrombocytopenia was associated with both laboratory evidence of hemorrhage (adjusted odds ratio [aOR]: 1.60, 95% CI: 1.38–1.86) and clinical evidence of hemorrhage (aOR: 1.68, 95% CI: 1.52–1.83). The odds of laboratory and clinical evidence of hemorrhage increased incrementally with severity of thrombocytopenia. Conclusion Thrombocytopenia is associated with both laboratory and clinical evidence of hemorrhage; risk increases dramatically as platelet count decreases.

Incidence, Management, and Risk Factors for Lower Gastrointestinal Bleeding in Renal Transplant Recipients

BackgroundThere are limited convincing data regarding management and outcomes of lower gastrointestinal bleeding (LGB) in renal transplant recipients (RTR). The aim of this study was to evaluate incidence, management strategies, and risk factors associated with LGB in RTR. MethodsBetween January 2004 and December 2013, RTR with LGB were analyzed. LGB was defined as having clinical evidence of hemorrhage after upper gastrointestinal etiology was ruled out. ResultsThere were 1578 RTR with a mean age of 50 ± 14 years at the time of transplantation. Mean follow-up time after transplantation was 57 ± 45 months. Forty-five (2.9%) patients had a documented site of LGB. The most common causes of bleeding were colitis and angiodysplasia (n = 17). Mean time to LGB after transplantation was 43 ± 36 months. Twelve patients with LGB required intervention. Three underwent colectomy, endoscopic treatment was utilized in 8, and 1 patient had angiographic embolization to control bleeding. Recurrent LGB developed in 11 patients of 42 patients who did not have surgery at the time of index bleeding. Surgical (n = 1) or endoscopic intervention (n = 4) was required in 5 of recurrent bleeders. LGB was more commonly seen in RTRs who had development of a nonfunctioning kidney (P < .0001). RTR who had an LGB had an increased overall mortality rate (not directly related to the bleeding episode) compared with those who did not have a LGB (P = .001). We did not observe any increased risk of LGB bleeding among patients who were receiving anticoagulant or anti-aggregant treatment agents (P = .76). ConclusionsNonfunctioning kidney after transplant is a risk factor for LGB. Overall mortality rates increased after LGB in RTR. Strategies aiming to prolong transplanted kidney function may reduce the incidence of LGB and improve life expectancy in RTR.

A Phase 1b (OX1222) Dose-Finding Study of OXi4503 Combined with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

IntroductionThe vascular disrupting agent OXi4503, induces apoptosis in malignant myeloblasts, removes their endothelial cell protection, and sensitizes blasts to the cytotoxic effects of cytarabine. Cogle et al confirmed the safety and feasibility of intravenous (IV) OXi4503 up to doses of 7.81 mg/m2 (maximum tolerated dose [MTD] not reached) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (data on file). Based on these data, a Phase 1b dose-finding study was initiated to evaluate the safety and tolerability of combined therapy with OXi4503 and cytarabine for a similar patient population.MethodsThe primary objective of this ongoing study (NCT02576301) was to determine the MTD of OXi4503 in combination with intermediate-dose cytarabine in patients with relapsed/refractory AML or MDS. Pharmacokinetic/pharmacodynamic studies and a preliminary assessment of efficacy were secondary endpoints. Escalating doses of OXi4503 (based on a modified Fibonacci scheme and beginning at 3.75 mg/m2) were administered IV over 10 minutes on Days 1 and 4. Fixed dose cytarabine (1 g/m2) was administered IV over 2 hours on Days 1-5 and preceded infusion of OXi4503 on Days 1 and 4. Cycles were repeated every 28 days. Part 1 of the study was opened for patients with relapsed/refractory AML or MDS (following failure of at least 1 prior hypomethylating agent) who had good organ function, ECOG performance status of 0-2, and normal values for PT and INR (based on bleeding events observed with single-agent OXi4503). Key exclusion criteria included acute promyelocytic leukemia, absolute peripheral blood myeloblast count >20,000/mm3, uncontrolled hypertension, prolonged QTc, history of recent significant CV events, history of hemorrhagic stroke, and any requirement for full dose anti-coagulation.ResultsBetween December 2015 and May 2016, 7 patients with relapsed/refractory AML were enrolled (6 evaluable). Median age was 51.5 years (range 26-68), 50% were male, 83% and 17% had ECOG performance status scores of 1 or 2, respectively. Subjects had failed a median of 4.2 (range: 2-6) prior therapies and all patients had intermediate- or adverse-risk cytogenetics. Five of 6 patients (83%) received 1 cycle of therapy while 1 patient received 2 cycles. Four of 6 patients (67%) withdrew from the study for progressive disease (PD) and 1 patient withdrew with stable disease (SD). The final patient achieved a morphological complete remission (mCR) after 2 cycles and proceeded to donor lymphocyte infusion. One patient in the 3.75 mg/m2 cohort experienced a dose-limiting toxicity of hypofibrinogenemia, but no clinical evidence of bleeding. Following correction with cryoprecipitate, fibrinogen returned to normal and remained normal without further intervention. The most common (>10% incidence) Grade 3/4 treatment-emergent adverse events attributable to the combination of OXi4503 and cytarabine included neutropenic fever, anemia, platelet count decrease, neutrophil count decrease, fibrinogen decrease, AST increase, hypokalemia, and D-dimer increase.ConclusionsThe vascular disrupting agent OXi4503 (3.75 mg/m2) in combination with cytarabine (1 g/m2/day) is generally well tolerated with preliminary evidence of activity in heavily pretreated, refractory AML patients. This Phase 1b study continues to recruit patients into the second cohort, OXi4503 (4.68 mg/m2) plus cytarabine (1 g/m2/day), as the optimal dose combination has yet to be defined. DisclosuresNo relevant conflicts of interest to declare.

Use of ISTH bleeding assessment tool to predict inherited platelet dysfunction in resource constrained settings

Background: The International Society of Thrombosis & Hemostasis (ISTH) bleeding assessment tool (ISTH-BAT) is used to record bleeding symptoms in patients with possible bleeding disorders.Aim: To investigate the utility of the ISTH-BAT in predicting platelet dysfunction in individuals with suspected inherited platelet function disorders.Method: Individuals with clinical evidence of bleeding and suspected inherited platelet function disorder and healthy volunteers were included in the study. The ISTH-BAT questionnaire was applied prior to light transmission aggregometry (LTA).Results: A total of 261 participants were included (100 healthy volunteers, and 161 with suspected inherited platelet function disorders). The ISTH-BAT score in participants with suspected inherited platelet function disorders (median 2; interquartile range [IQR] 5–1) was significantly higher than in healthy volunteers (median 0; IQR 2–0). There was also a significant difference between participants with suspected inherited platelet function disorders with a platelet defect detected by LTA (median 4; IQR 8–3) and those with normal platelet function (median 2; IQR 3–1) (p < 0.001). The ISTH-BAT score was associated with a demonstrable platelet defect on platelet function testing (area under the receiver operating characteristic curve = 0.8 [95% confidence interval 0.72–0.87, p = < 0.001] and odds ratio 3.25 [95% confidence interval 2.13–4.37, p = < 0.001]).Conclusion: The ISTH-BAT is a useful tool for documenting bleeding symptoms and the score obtained is also predictive of the presence of a platelet defect on LTA in patients with suspected inherited platelet dysfunction.

Managing Acquired Haemophilia (A): Pan London Experience-Relating to the European Acquired Haemophilia (EACH2) Registry Data

▪BackgroundAcquired haemophilia A (AHA) is a rare and potentially fatal bleeding disorder characterised by the development of autoantibodies directed against factor VIII. The optimal treatment for AHA remains uncertain and there is a paucity of published data to guide clinical practice. The EACH2 Registry has provided the largest observational dataset from 117 European centres on the management of AHA. The aim of this study is to provide retrospective analysis of the experience of all Haemophilia Centres across London on the management of AHA and compare it to the data presented in the EACH2 Registry.MethodWe performed a multicentre centre retrospective analysis of all AHA patients presenting between January 2009 and December 2012 to Haemophilia Centres across London. Data collected included demographics, aetiology, bleeding characteristics immunosuppression and haemostatic agents used to control the first bleeding episode.ResultsThere were 65 patients identified. The median (IQR) age at diagnosis was 78 (57-85) years. At presentation, the median haemoglobin concentration, FVIII:C and inhibitor titre were 80 g/L (68-100), 2 IU/dl (0-5.5) and 13.0BU/ml(3.5-47 ).At presentation 48/65 patients demonstrated bleeding from multiple sites with 18/65 experiencing life-threatening bleeds. 4 patients had no evidence of clinical bleeding and there was no difference in haemoglobin level, baseline FVIII:C and peak inhibitor titre compared to those who bled(P>0.05). 50% of patients had idiopathic cause of AHA with malignancy being the second most common.Around 50% (33/65) of patients were treated with activated prothrombin complex concentrate (aPCC) alone and 19/65 patients alternated between aPCC and recombinant activated FVII (FVIIa). 6(9%) patients with bleeding symptoms were managed with tranexamic acid or desmopressin alone without bypassing agents.There median (IQR) time to treatment response (defined as days to factor VIII >50IU/dl or negative Bethesda) was 45(23-82) days. Single agent prednisolone was most common (32/64) immunosuppression used followed by combination therapy with prednisolone and cyclophosphamide (22/64).87% of patients achieved treatment response. A higher proportion of patients (21/22) treated with prednisolone and cyclophosphamide achieved response compared to prednisolone alone (29/33). There was no difference in the days to response (83 vs 69 p=0.055), time to remission (days to stopping immunosuppression)(123 vs 1958 p=0.065), incidence of relapses (7/32 vs 5/22) or duration of sustained remission (264 vs 204 p= 0.42) between the 2 groups. 8 patients received rituximab in addition to prednisolone and/or cyclophosphamide and 3 was treated with rituximab alone.16% (12/65) of patients relapsed. These patients exhibited a higher mean baseline and peak inhibitor (BU/ml) (140 vs 54 p=0.011, 143vs 64 p=0.03) There was no difference in the time to response (78vs94 p=0.50) between patients who relapsed compared to those who did not. Presenting inhibitor of >16BU was also associated with longer days to treatment response(121 vs 58 p=0.001)70% of patients were alive at follow up with similar portions seen in the between the cyclophosphamide and prednisolone group and prednisolone only group. [Display omitted] [Display omitted] Summary:Our study reinforced the findings of the EACH2 Registry that FVIII level and inhibitor tire did not correspond to the presence of bleeding or the severity of bleeding. However a low presenting inhibitor titre <16BU/ml was associated with faster inhibitor eradication and normalisation of FVIII. A higher baseline and peak inhibitor titre also influenced the rate of relapse. Bypassing agents were used to treat 91% of our patients with clinical bleeding, unlike only 70% in the EACH2 registry.70 % of patients in the registry were treated with rFVIIa alone, which was observed in only 8% of our patients. The majority of our patients receive aPCC or alternating treatment between aPCC and rFVIIa. This selection preference for aPCC may be reflected by difference in the half life between the bypassing agents.In contrast to the EACH2 Registry, we did not observe a shorter time to treatment response, a reduction in relapse rate or an increase in duration of sustained remission with the addition of cyclophosphamide to prednisolone.Despite this, our study does concur with the EACH2 Registry that the final survival outcome was not affected by the choice of first line immunosuppression. DisclosuresLuo:Grifols: Research Funding. Austin:Baxter: Speakers Bureau; Novonordisk: Honoraria, Speakers Bureau. Hart:Baxter: Speakers Bureau; Octapharma: Research Funding, Speakers Bureau; Novo Nordisk: Speakers Bureau; Pfizer: Speakers Bureau. Batty:Octapharma: Research Funding.

Warfarin-related nephropathy: Prevalence, risk factors and prognosis

Warfarin has been the most commonly prescribed oral anticoagulantsince its approval in 1954 [1]. Warfarin is widely used in the preventionand treatment of deep venous thrombosis and pulmonary embolism,thromboembolismpreventioninthepatientswithatrial fibrillation,pros-thetic heart valves and indwelling central venous catheters. It interruptsthe synthesis of coagulation factors (II, VII, IX, and X) by inhibiting thevitamin K epoxide reductase (VKOR) and causes disruption of the extrin-sicclottingcascade.Warfarinisstillun deruseinclinicalpracticeespeciallyin China despite the strong evidence of this drug for thromboembolismprevention [2].Thismaybeduetoitsnarrowtherapeuticrange,potentialinteractions with a variety of commonly used drug and food [3], and itspropensity to cause hemorrhage. Also, different warfarin-relatedgenotypes were also related to over-anticoagulation and hemorrhagiccomplications [4].Warfarin-relatednephropathy(WRN)isarecentlyrecognizedcom-plication during warfarin anticoagulation therapy, in which excessivewarfarinization [international normalized ratio (INR) N3.0] leads toacute kidney injury (AKI) by causing glomerular hemorrhage andrenal tubular obstruction by red blood cell (RBC) casts [5,6]. Brodskyet al. [7] was the first to describe this entity through kidney biopsy ina subset of patients with warfarin overdose, hematuria, and AKI, andeachbiopsyspecimendemonstratedtheevidenceofacutetubularinju-ry, glomerular hemorrhage and renal tubular obstruction by RBC casts.They termed clinical WRN as an episode of unexplained acute renalinjury defined as a serum creatinine increase greater than 0.3 mg/dlwithin one week of an INR measurement greater than 3.0 in a patientbeing treated with warfarin without clinical evidence of hemorrhage[5,6]. They also established an animal model of WRN, and showed theexcessive anticoagulation increased serum creatinine levels andhematuriainthe5/6nephrectomyratsbutnotincontrols,whichresultedin the formation of obstructing tubular RBC casts [8].However, WRN could be the result of a problem more widespreadthan complete tubular obstruction by RBCs. Other potential mecha-nismsmayparticipateintheoccurrenceofWRN(Fig.1).First,oxidativestress damage to tubules by RBC, even though the RBC did not obstructthetubule,couldleadtoWRN[9].Thepatientswithchronickidneydis-ease have reduced plasma antioxidant enzyme activities, such as gluta-thioneperoxidaseandcatalase,whichmaycontributetoahigherriskofWRN. Other important mechanisms, including atheroembolism [10],interstitial nephritis [11], apoptosis of glomerular endothelial cells [8]and direct effects of warfarin on the glomerulus [12] may also contrib-ute to the development of WRN. Warfarin has been shown to affectglomerular mesangial cells by interfering with the activation of theproduct of growth arrest-specificgene6[11]. This could affect glomer-ular hemodynamics or aggravate the underlying glomerular disease.Brodsky et al. [5] further investigated the prevalence, risk factors,and consequence of WRN in a large cohort of patients who initiatedwarfarin therapy during a 5-year period at the Ohio State UniversityMedical Center, WRN occurred in 20.5% of the entire cohort, 33.0% ofthe CKD cohort, and 16.5% of the non-CKD cohort, which indicatedthat patients with CKD are at much greater risk of WRN than thosewithout CKD. It suggests that CKD patients may be prone to over-anticoagulation as spend less time within the target range, requiredmorefrequentadjustmentsandhadhigherbleedingrisk.Otherriskfac-torsfor WRNincludedage, diabetesmellitus,hypertension,andcardio-vascular disease. Therefore, WRN may be a common complication ofwarfarin therapy in high-risk patients, especially in the CKD patients.Recently, An et al. [13] showedWRNdeveloped in19.3% of thepatientshavingexcessivewarfarinization.Alowerbaselineserumalbumin,highserum AST at post INR elevation, and heart failure were independentrisk factors for WRN. In contrast, atrial fibrillation significantlydecreased the risk of WRN. However, neither the presence of CKD norbaseline estimated glomerular filtration rate (eGFR) was an indepen-dent risk factor for WRN.The occurrence of WRN also increased long-term mortality in pa-tients with and without CKD. Brodsky et al. [5] reported that one-yearmortality was significantly higher in the patients with WRN compared

Safety and efficacy of catheter directed thrombolysis in children with deep venous thrombosis

Safety and efficacy of catheter directed thrombolysis in children with deep venous thrombosis

Prospective Evaluation of Coagulation in Critically Ill Neonatal Foals

Coagulopathy is a potentially underrecognized complication of sepsis and septic shock in critically ill neonatal foals. Critically ill neonatal foals have abnormalities in coagulation that are associated with disease severity and outcome. Foals <72 hours old admitted to a neonatal intensive care unit. Prospective, observational study. Blood was collected at admission, 24, and 48 hours for platelet count, prothrombin time, activated partial thromboplastin time, antithrombin activity and concentrations of fibrin degradation products, and fibrinogen in plasma from all foals. Sixty-three foals were enrolled and classified as Septic Shock (12), Septic (28), and Other (23). At least 1 abnormal value was found in 18/28 (64%) samples from the Septic Shock group, 66/85 (78%) from the Septic group, and 30/59 (51%) from the Other group (P= .01). Coagulopathy (3 or more abnormal values) was present in 7/28 (25%) samples in the Septic Shock group, 14/85 (16%) samples in the Septic group, and 3/59 (5%) samples in the Other group (P= .0028). Clinically detectable bleeding occurred in 8/12 (67%) Septic Shock cases, 11/28 (39%) Septic cases, and 3/23 (13%) Other cases (P= .009). Foals in Septic Shock were 12.7 times more likely to have clinical evidence of bleeding than those in the Other group (95% CI 2.3-70, P= .004). Treatment with fluids or plasma did not have a detectable effect on coagulation values. Coagulopathy commonly occurs in critically ill neonatal foals, especially those with sepsis and septic shock.

Colonoscopic Treatment of Acute Diverticular Hemorrhage

Purpose: Although colonoscopy is routinely used in the diagnostic evaluation of patients with suspected diverticular hemorrhage, data are limited concerning colonoscopic treatment of acute diverticular bleeding. Previous reports of colonoscopic hemostasis for diverticular hemorrhage have mostly consisted of thermocoagulation and/or epinephrine injection. We report our experience using a relatively newer technique: endoclips. Methods: We reviewed colonoscopy records of all inpatients from March 2004-March 2005 who underwent colonoscopy for evaluation of overt lower GI bleeding within the University of California San Francisco Hospital system. We identified those with the colonoscopic diagnosis of acute diverticular hemorrhage, defined as findings of active bleeding or a nonbleeding visible vessel from/within a diverticulum. The following data were retrospectively collected: patient demographics, procedural findings, endoscopic treatment techniques and success, and hospital course. Results: Ten patients (9M/1F) had acute diverticular hemorrhage at colonoscopy. Their mean age was 71.7 years and the majority (70%) had comorbid cardiopulmonary, liver, and/or renal diseases. Patients underwent urgent colonoscopy at a median time of 20 hours after presentation and required a mean of 5 units packed red cell transfusion prior to procedure. At colonoscopy, all diverticula were vigorously irrigated, diverticular clots were removed (using irrigation, mechanical instruments, or suction), and all were meticulously examined. Active diverticular bleeding was identified in six patients, and a visible vessel was identified in four patients. Bleeding sites were located in the ascending colon (4), transverse colon (3), descending colon (1), and sigmoid colon (2). All diverticular bleeding sites were successfully treated with endoclips with or without dilute epinephrine injection (used in 70%). There were no procedure-related complications. All patients were discharged within three days without further clinical evidence of bleeding, transfusion requirements, or need for additional endoscopic, angiographic, or surgical therapy. Conclusions: Colonoscopic treatment of patients with acute diverticular hemorrhage using endoclips appears to be effective and safe. Urgent colonoscopy should be considered in patients with suspected diverticular hemorrhage, as it may enable treatment without need for more invasive therapeutic measures.

Pharmcokinetics of Fondaparinux by Anti-Xa Levels and Clinical Response to Anticoagulation in a 4-Month Old Congenital Cardiac Patient with Heparin-Induced Thrombocytopenia (HIT) and Established Venous Thrombosis Transitioned from Argatroban to Fondaparinux.

Our group has recently reported on heparin-induced thrombocytopenia (HIT) as an emerging cause of morbidity and mortality in pediatric cardiac surgery patients (Alsoufi, Ped Card Surg Ann of Sem Thorac Cardiovasc Surg 2004: 7: 155). This has included our experience with the off-label use of the antithrombin argatroban as an initial alternative anticoagulant to heparin in neonates and young children with HIT. Our findings indicate the incidence of HIT in pediatric patients undergoing congenital cardiac surgery to be 1–2% with a thrombotic rate of 50–60%. As with adults, children > 1 year with HIT-related thrombosis needing intermediate-to-longterm anticoagulation can be transitioned to warfarin. However stable warfarinization of children < 1 year is difficult, particularly given the feeding difficulties seen in sick congenital cardiac patients. In one such 4 month old, reported here, we successfully used the pentasaccharide fondaparinux, verifying dosage according to fondaparinux levels as measured by a specific fondaparinux curve. A 3 month old 3 kg girl with Down's syndrome underwent cardiac surgery with cardiopulmonary bypass at our institution (complete atrio-ventricular canal repair, closure of patent ductus arteriosus and patent foramen ovale). Platelets did not rise to baseline levels post-operatively and functional HIT assay was positive on postoperative day (POD) 8. All heparin was stopped and anticoagulation with argatroban initiated after obtaining parental informed consent. Due to IV access issues and necessity for pacemaker insertion argatroban was administered with interruptions. On POD 11 the patient thrombosed a PICC line in her left thigh. The line was surgically removed, but residual non-occulsive thrombus was noted by vascular ultrasound in the left common and proximal femoral veins, which persisted on reimaging 1 week later despite sustained therapeutic argatroban infusion. To facilitate outpatient management a decision was made to attempt transition to fondaparinux. Renal function was normal. After obtaining parental informed consent therapy with fondaparinux ( t 1/2 =17−l20 hr) was initiated at 0.15 mg/kg q 24 hrs on POD 23. Anti-Xa levels were drawn at 2, 4, 8 hr post injection and then at intervals on days 2, 3, 4 and 7 of fondaparinux therapy (see table). Values were referenced against both a fondaparinux and a low molecular weight heparin (lovenox) curve. Coefficient of correlation between curves: r = 0.939. The patient did well clinically on fondaparinux with no evidence of bleeding and was discharged on POD 30. Vascular ultrasound showed complete resolution of thrombus at the time of discharge. Platelets remained stable. The patient continued on outpatient fondaparinux therapy for 3 months with stable platelet counts and no clinical evidence of bleeding or rethrombosis.Response to fondaparinux by anti-Xa levelsDay of therapyHour post injectionFondaparinux Level (fondaparinux curve)Corresponding level on LMWH curveDay 120.330.4140.470.5080.60.60Day 220.70.7340.660.6980.510.51Day 3pre0.180.1950.670.60Day 4pre0.180.3320.710.72Day 520.77not done

Hemorrhage associated with vitamin C deficiency in surgical patients

Background. Diffuse hemorrhage in surgical patients with normal coagulation parameters may be caused by vitamin C deficiency and is rapidly reversed by vitamin C replacement. Methods. Patients treated on a surgical service were entered into a clinical registry over a 12-month period if they experienced diffuse hemorrhage in the face of normal coagulation parameters and a plasma ascorbic acid level < 0.6 mg/dL (normal 0.6-2.0 mg/dL). Oral vitamin C replacement was administered after determination of plasma ascorbic acid level. Response to therapy, including subsequent bleeding events, need for blood transfusions, and demographic data including social and dietary history were retrospectively reviewed from hospital and outpatient clinic records. Results. Twelve patients with bleeding diatheses and low plasma ascorbic acid levels were identified. Plasma ascorbic acid levels were 0.1 to 0.5 mg/dL (mean, 0.3 mg/dL). There were 6 men and 6 women; age ranged from 46 to 90 years (mean, 78 years). Coagulation parameters were normal in all patients. Diffuse postoperative bleeding from nonsurgical causes was evident in 10 of 12 patients. Four patients, 2 of whom had operations, presented with chronic recurrent blood loss from the gastrointestinal tract. Each patient received 250 to 1000 mg of vitamin C replacement daily. Within 24 hours of vitamin C administration, there was no further evidence of clinical bleeding nor need for subsequent blood transfusions in any patient. Conclusions. Vitamin C deficiency should be included in the differential diagnosis of nonspecific bleeding in surgical patients. Prolonged hospitalization, severe illness, and poor diet create vitamin C deficiency with significant clinical consequences. Oral vitamin C replacement rapidly reverses the effects of this disorder. (Surgery 2002;131:408-12.)