Supratherapeutic Anticoagulation Research Articles

A career in solving clinical-pathological conundrums: Heyde syndrome, anti-platelet factor 4 disorders, and microvascular limb ischemic necrosis.

Hematology is a clinical specialty with strong roots in the laboratory; accordingly, the lab can help solve perplexing clinical problems. This review highlights clinical-pathological conundrums addressed during my 35-year hematology career at McMaster University. Heyde syndrome is the association between aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia where the bleeding is usually cured by aortic valve replacement; the chance reading of a neonatal study showing reversible deficiency of high-molecular-weight (HMW) multimers of von Willebrand factor (vWF) following surgical correction of congenital heart disease provided the key insight that a subtle deficiency of HMW multimers of vWF explains Heyde syndrome. The unusual immunobiology of heparin-induced thrombocytopenia (HIT)-a highly prothrombotic, antibody-mediated, anti-platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin-dependent platelet-activating antibodies-permitted identification of key clinical features that informed development of a scoring system (4Ts) to aid in HIT diagnosis. Atypical clinical presentations of HIT prompted identification of heparin-independent anti-PF4 antibodies, now recognized as the explanation for vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as VITT-like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep-vein/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT- and cancer-associated venous limb gangrene provided insight into disturbed procoagulant/anticoagulant balance; these concepts are relevant to microvascular thrombosis in critical illness (symmetrical peripheral gangrene), including a pathophysiological role for proximate "shock liver" (impaired hepatic synthesis of natural anticoagulants).

Supra-therapeutic Anticoagulation with Warfarin: A Cross-sectional Study.

To identify the extent and associated factors for patients with prolonged prothrombin time, international normalized ratio (PT-INR), and the dosage modifications were carried out with warfarin. Studies evaluating patients on warfarin with supratherapeutic anticoagulation are limited. It is vital to understand the management strategies for patients receiving warfarin who are bleeding and those with only supratherapeutic PT-INR. To evaluate the factors associated with supratherapeutic anticoagulation without bleeding with warfarin. A cross-sectional study was carried out on patients receiving long-term warfarin with at least one PT-INR value > 3.2. Percent time in therapeutic range (TTR) was calculated and National Institute for Health and Care Excellence (NICE) guidelines were adhered to defining anticoagulation control into good (> 65%) and poor (< 65%). One hundred and forty-four patients were recruited. Nearly half of the study population had PT-INR values between 3.2 and 3.9. On average, individuals had at least 4 times PT-INR values in the supratherapeutic range. Elderly patients were observed with a significant trend of supratherapeutic INR. Duration of therapy was significantly correlated with the risk of PT-INR > 4. Lower TTR was observed in patients with frequent PT-INR > 4 and those patients had significantly poor anticoagulation control. Duration of warfarin therapy and HAS-BLED scores were observed to be significant predictors of supratherapeutic INR. Large variations were observed in the modifications of warfarin dose carried out at various supratherapeutic INR values and consequently PTINR values. We observed that the majority of patients with supratherapeutic INR had their INR values between 3.2 and 3.9. Elderly patients, with higher HAS-BLED scores and prolonged duration of warfarin therapy, were observed with an increased risk of supratherapeutic anticoagulation. Careful dosage modifications are needed particularly in high-risk categories as mentioned above.

Analysis of Bicarbonate-Based Purge Solution in Patients With Cardiogenic Shock Supported Via Impella Ventricular Assist Device.

The Impella device is a continuous axial flow pump which provides hemodynamic support by expelling blood into the aorta. The manufacturer recommends using dextrose-based heparin containing solutions as the default purge. As an alternative to anticoagulant solutions, a bicarbonate-based purge solution has been proposed with limited data substantiating adequate protection and durability. To assess the impact of a bicarbonate-based purge solution on Impella pump thrombosis and bleeding outcomes. Single-center, retrospective study of cardiogenic shock patients who received an Impella between December 2020 through September 2021. Patients were evaluated based on whether they received bicarbonate-based purge solutions or remained on heparin-based purge solutions. The primary outcome was the rate of Impella pump thrombosis, defined as multiple purge pressures greater than 800 mm Hg. Secondary outcomes included incidence of bleeding defined as a drop in Hgb of at least 2 g/dL along with use of blood products and supratherapeutic anticoagulation defined as an aPTT of greater than 70 seconds. Forty-three patients received bicarbonate-based purge solutions and 49 controls received heparin. The incidence of purge thrombosis by purge pressure threshold was similar between the two groups (16.3% vs 12.2%, P = 0.58). The rate of bleeding was lower with bicarbonate-based purge (27.9% vs 65.3%, P < 0.05) driven by a drop in Hgb of more than 2 g/dL. The rate of supratherapeutic anticoagulation was higher in the heparin arm (65.3% vs 27.9%, P < 0.05). Nonanticoagulant purge alternatives offer the potential to reduce bleeding complications and laboratory monitoring burden while maintaining durability.

Review of time in therapeutic range of warfarin in a tertiary centre in Malaysia

Anticoagulation management is a recognized challenge in medical care. Complications of supratherapeutic anticoagulation are hemorrhagic stroke, major bleeding, and death. There is an even greater risk of ischemic stroke in AF, worsening of VTE associated with subtherapeutic dosing.

Anti-Xa levels in critically ill children receiving enoxaparin for venothromboembolism prophylaxis

Venothrombolism (VTE) prophylaxis is increasingly utilized in pediatric intensive care units (PICUs). Enoxaparin, a low-molecular weight heparin, is frequently used for this purpose. Enoxaparin can also be used for therapeutic anticoagulation in cases of known thrombus. In such cases, monitoring involves obtaining serum anti- Xa levels with a target value of 0.5–1 units/mL. No monitoring recommendations currently exist for enoxaparin when intended for pediatric VTE prophylaxis. We hypothesize that a clinically important number of patients on VTE prophylaxis with enoxaparin have serum anti-Xa levels consistent with values targeted for therapeutic anticoagulation.We found that over 20% of patients on VTE prophylaxis with enoxaparin had serum anti-Xa levels consistent with true therapeutic anticoagulation (anti-Xa level 0.5–1 units/mL) during their enoxaparin course and 5% achieved values of supratherapeutic anticoagulation (anti-Xa level >1 units/mL). Serum anti-Xa level did not correlate with once versus twice daily dosing, body mass index (BMI), or creatinine level. Blood urea nitrogen (BUN) was found to have a positive odds ratio for an anti-Xa level ≥ 0.5 units/mL.We believe that this incidence of unintended therapeutic anticoagulation indicates a clinically significant number and therefore routine anti-Xa evaluation while on VTE prophylaxis is warranted within our population.

Thromboprophylaxis in congenital nephrotic syndrome: 15-year experience from a national cohort

IntroductionCongenital nephrotic syndrome (CNS) is an ultra-rare disease associated with a pro-thrombotic state and venous thromboembolisms (VTE). There is very limited evidence evaluating thromboprophylaxis in patients with CNS. This study aimed to determine the doses and duration of treatment required to achieve adequate thromboprophylaxis in patients with CNS.MethodsFrom 2005 to 2018 children in Scotland with a confirmed genetic or histological diagnosis of CNS were included if commenced on thromboprophylaxis. The primary study endpoint was stable drug monitoring. Secondary outcomes included VTE or significant haemorrhage.ResultsEight patients were included; all initially were commenced on low-molecular weight heparin (enoxaparin). Four patients maintained therapeutic anti-Factor Xa levels (time 3–26 weeks, dose 3.2–5.07 mg/kg/day), and one patient developed a thrombosis (Anti-Factor Xa: 0.27 IU/ml). Four patients were subsequently treated with warfarin. Two patients maintained therapeutic INRs (time 6–11 weeks, dose 0.22–0.25 mg/kg/day), and one patient had two bleeding events (Bleed 1: INR 6, Bleed 2: INR 5.5).ConclusionsAchieving thromboprophylaxis in CNS is challenging. Similar numbers of patients achieved stable anticoagulation on warfarin and enoxaparin. Enoxaparin dosing was nearly double the recommended starting doses for secondary thromboprophylaxis. Bleeding events were all associated with supra-therapeutic anticoagulation.

Phlegmasia cerulea dolens associated with acute coronavirus disease 2019 pneumonia despite supratherapeutic warfarin anticoagulation

Patients with acute coronavirus disease 2019 (COVID-19) respiratory infection are associated with concomitant thromboembolic complications and a hypercoagulable state. Although these mechanisms are not completely understood, unique alterations in the serum markers for hemostasis and thrombosis have been detected. A high index of suspicion is required by vascular surgeons for patients presenting with this novel virus. We present the case of a 51-year-old man with acute COVID-19 pneumonia who developed phlegmasia cerulea dolens despite chronic warfarin therapy and a supratherapeutic international normalized ratio.

Factors associated with therapeutic anticoagulation status in patients with ischemic stroke and atrial fibrillation

Background and purposeUnderstanding factors associated with ischemic stroke despite therapeutic anticoagulation is an important goal to improve stroke prevention strategies in patients with atrial fibrillation (AF). We aim to determine factors associated with therapeutic or supratherapeutic anticoagulation status at the time of ischemic stroke in patients with AF. MethodsThe Initiation of Anticoagulation after Cardioembolic stroke (IAC) study is a multicenter study pooling data from stroke registries of eight comprehensive stroke centers across the United States. Consecutive patients hospitalized with acute ischemic stroke in the setting of AF were included in the IAC cohort. For this study, we only included patients who reported taking warfarin at the time of the ischemic stroke. Patients not on anticoagulation and patients who reported use of a direct oral anticoagulant were excluded. Analyses were stratified based on therapeutic (INR ≥2) versus subtherapeutic (INR <2) anticoagulation status. We used binary logistic regression models to determine factors independently associated with anticoagulation status after adjustment for pertinent confounders. In particular, we sought to determine whether atherosclerosis with 50% or more luminal narrowing in an artery supplying the infarct (a marker for a competing atherosclerotic mechanism) and small stroke size (≤ 10 mL; implying a competing small vessel disease mechanism) related to anticoagulant status. ResultsOf the 2084 patients enrolled in the IAC study, 382 patients met the inclusion criteria. The mean age was 77.4 ± 10.9 years and 52.4% (200/382) were women. A total of 222 (58.1%) subjects presented with subtherapeutic INR. In adjusted models, small stroke size (OR 1.74 95% CI 1.10–2.76, p = 0.019) and atherosclerosis with 50% or more narrowing in an artery supplying the infarct (OR 1.96 95% CI 1.06–3.63, p = 0.031) were independently associated with INR ≥2 at the time of their index stroke. ConclusionSmall stroke size (≤ 10 ml) and ipsilateral atherosclerosis with 50% or more narrowing may indicate a competing stroke mechanism. There may be important opportunities to improve stroke prevention strategies for patients with AF by targeting additional ischemic stroke mechanisms to improve patient outcomes.

Spontaneous hemopericardium with fatal tamponade physiology in end-stage renal disease patient on warfarin: a case report

Cardiac tamponade (CT) is a medical emergency. Although frequently challenging, timely clinical diagnosis and efficient management are essential elements of successful treatment. We report the case of an 87-year-old male with history of end-stage renal disease (ESRD) on hemodialysis, severe coronary artery disease requiring multiple percutaneous interventions and paroxysmal atrial fibrillation on therapeutic warfarin, who presents over the course of three months with recurrent severe hemodialysis-related hypotension and crushing substernal chest pain compromising his hemodialysis sessions. Electrocardiograms had been consistent with atrial fibrillation, transthoracic echocardiogram with moderate aortic stenosis, pharmacologic stress test and left heart catheterization with normal perfusion and non-obstructive coronary artery disease, respectively. On last admission, creatinine was 5.43 mg/dL, blood urea nitrogen 34 mg/dL, international normalized ratio (INR) 5.14, partial thromboplastin time (PTT) 65.1 s and troponin I 0.034 ng/mL. Patient continued to deteriorate hemodynamically despite cautious resuscitation and intermittent pressor support. Pertinent work-up was negative. On hospital day five, bedside cardiac echocardiogram revealed a large pericardial effusion with right atrial and ventricular collapse consistent with CT. Upon preparation for emergent pericardiocentesis, patient went to recurrent pulseless electrical activity (PEA) and succumbed to a ventricular fibrillation arrest shortly thereafter. Autopsy was more consistent with uremic effusion but a spontaneous hemopericardium in the setting of supratherapeutic anticoagulation could not be ruled out. Early recognition of pericardial effusions can prevent life-threatening complications and spur urgent intervention. Point-of-care echocardiography is really crucial for timely decision making. Clinicians should maintain a high level of suspicion for uremic pericardial effusions and make any effort to restore intensive hemodialysis sessions for the effusion to abate, unless tamponade physiology has developed, in which case ultrasound- or fluoroscopy-guided pericardiocentesis or pericardial window might be life saving. New guidelines with stricter criteria on the initiation of therapeutic anticoagulation in ESRD might be warranted.

Anticoagulation of a Percutaneous Left Ventricular Assist Device Using a Low-Dose Heparin Purge Solution Protocol: A Case Series

Background Impella CP® is a percutaneous left ventricular assist device that requires a heparin–dextrose purge solution. The manufacturer recommends heparin 50 units/mL, but supratherapeutic anticoagulation has been observed with this concentration. Objective The purpose of this evaluation was to observe the efficacy and safety of a low-dose heparin-based purge solution (25 units/mL in dextrose 20%). The primary outcome evaluated percentage of activated clotting times (ACTs) below therapeutic range. Secondary objectives included evaluating the incidence of device thrombosis and rate of heparin-induced thrombocytopenia (HIT). Platelet trends were characterized. Methods A single-site retrospective review was conducted for all adults with the Impella CP from January 2015 to December 2017. Results A total of 18 patients were included. The percentage of ACT readings within goal of 160 to 200 seconds was 49%, and 38% of readings were subtherapeutic. Per BARC bleeding criteria, 22% (n = 4) patients experienced class IIIa bleeding and 39% (n = 7) experienced class II bleeding. Though 4 (22%) patients were tested for HIT, no patients were positive. Patients showed universal reductions in platelet counts. Conclusions The use of a low-dose anticoagulation protocol of heparin 25 units/mL in dextrose 20% as needed warrants further evaluation.

Analysis of Factors That Interrupt With INR Control in the First Anticoagulation Clinic Monitoring Jordanian Patients.

Multiple factors such as vitamin K consumption, drug interactions, herbs interactions, disease states, and alcohol intake affect international normalized ratio (INR) values and thus warfarin dosing. These variables have been described in general and for all patients in the literature. In contrast, the factors that affect INR control in a specific population are rarely studied. Being aware of these factors contributes a lot in maintaining an INR control and avoiding the supratherapeutic or subtherapeutic anticoagulation and the associated risks of hemorrhage or thromboembolism. The aim of this study is to recognize the specific population factors in Jordanian patients that interrupt INR control. Such recognition provides clinical pharmacists managing the anti-coagulation clinic (ACC) with necessary tools and predictors of dose adjustment, nontarget INR handling, and points to add on to the educational session. A total of 2788 patients were referred to the first clinical pharmacists managed ACC at Queen Alia Heart Institute—the only official referral hospital for cardiac patients in Jordan—for education and monitoring between November 1, 2013, and November 1, 2016. We evaluated specific population factors that interrupt INR control using a pretested, structured clinical data collection form. The patients were followed up regularly for achieving target INR (TINR). For patients who were not achieving TINR, the possible cause was examined thoroughly by reviewing the patient’s medical file for recent medication intake, comorbidities, and laboratory results. Then the patients or their caregiver were asked direct questions regarding their diet, food supplements, cigarette smoking, shisha smoking, alcohol intake, herbs, and complementary medicine use and compliance, in addition to performing pharmacogenetic testing (polymorphisms of vitamin K–epoxide reductase complex [VKORC1] and cytochrome P450 2C9 [CYP2C9] genes) in special cases. For a total of 2788 patients, 89 488 INR values were included in the study. Of all, 20 365 (22.8%) were non-TINR values, 13 145 (14%) were subtherapeutic, and 7220 (8.1%) were supratherapeutic. All patients included in the study had a non-TINR at least 3 times (n = 65, 2.3%) and as frequent as 50 times (n = 21, 0.8%) during the study period. Non-TINR values ranged from 1 to 11. Serious side effects reported in 7 patients with uncontrolled INR, 6 were bleeding, which required hospitalization (2 upper gastrointestinal [GI] bleeding, 3 nasal bleeding, and 1 eye bleeding), 1 was cerebrovascular accident (CVA thrombolytic). Factors that interrupted INR control in our population, arranged in descending sequence, were concurrent medication use 46.9% (mainly Salicylates and Amiodarone), smoking cigarettes and shisha 17% (represented the most frequent single factor that caused non-TINR in the present study), a nonbalanced dietary vitamin K intake 16.88% caused changes in INR (lower) was related to an increase in the intake of vitamin K-rich food, were noticed to be much more in the spring season in Jordan (end of March and April mainly), herbal supplements 15.02%; Hawthorn (Crataegus, الزعرور) is an herb that lives widely in Jordan, and shockingly we found that it is used very commonly in our ACC patients and corresponded to an elevated INR <8 in 11 patients, and serious bleeding events that required hospitalization in 2 cases), noncompliance 1.49%, comorbid diseases 1%, malabsorption 0.53%, alcohol intake 0.39%, and VKORC1 A/G and CYP2C9 *1*1 genotype 0.15%. The analysis of factors that interrupted with INR control in our patients were both predicted and distinctive; most of these factors were reported previously by other researchers. On the other hand, many of the previously reported factors were not frequently detected in our patients, and the frequency of each of the realized factors was contributed differently to non-TINR in our population. Alarming factors causing non-TINR detected in our study include smoking both cigarettes and shisha, herbal use (Hawthorn and Ginseng), increased intake of vitamin K rich food in the spring season, and concurrent medication use (Salicylates, Amiodarone, Ciprofloxacin, nonsteroidal anti-inflammatory drugs [NSAIDS], Azithromycin, Clarithromycin: although the use of these drugs is mandatory sometimes, it can be replaced by an alternative, eg, antibiotics or monitored closely together with warfarin).

SPONTANEOUS HEMORRHAGE INTO GIANT EMPHYSEMATOUS BULLA

SESSION TITLE: Obstructive Lung Diseases SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Pulmonary bullae are seen in emphysematous lungs and are usually of little consequence unless complicated by infection, pneumothorax or hemorrhage. Spontaneous hemorrhage into large emphysematous bullae has been rarely reported in patients with pre-existing coagulopathies or supra-therapeutic anticoagulation. CASE PRESENTATION: We present a 57-year-old man with history of severe bullous emphysema and peripheral artery disease on aspirin and warfarin who presented to the emergency department for massive hemoptysis. He coughed up about 3 cups of blood at home and continued to have hemoptysis in the hospital. Computed tomography angiography revealed fluid and mass like consolidations within a giant bullous lesion in right upper lung that was new from 3 days ago. He was hemodynamically stable, with a stable hemoglobin. His warfarin was held and was given intravenous vitamin K. He was monitored closely in the intensive care unit and was discharged home after a few days of stability. DISCUSSION: Bullous emphysema, also known as vanishing lung syndrome occurs due to lung damage from smoking. Lung parenchyma and airway destruction in emphysema results in stretching and breakage of alveolar walls creating large air spaces that cannot handle normal gas exchange during respiration. This results in incomplete exhalation and air trapping in the lungs that progressively enlarge, forming large bullae. Complications include infections, pneumothorax or hemorrhage.Pulmonary hemorrhage is most often due to blunt or penetrating chest trauma or associated with ruptured vascular malformations or infections particularly tuberculosis and fungal. Spontaneous hemorrhage into pre-existing emphysematous bullae has been described in patients with coagulation abnormalities, supra-therapeutic anticoagulation or anti-platelet agents. The most likely mechanism is infection causing angionecrosis within the bulla and thereby bleeding. After initiating supportive care, control of the bleeding can be achieved by coil embolization. Due to the rare possibility of pulmonary artery aneurysms pulmonary arteriography may be required if bronchial arteriography does not reveal abnormalities. Surgical resection of the lobe may be required if bleeding cannot be stopped. CONCLUSIONS: Spontaneous hemorrhage is a rare complication of large emphysematous bullae particularly in the setting of coagulation abnormalities, which can result in life threatening bleeding. Management involves correcting coagulopathy and coil embolization or surgical lobectomy if bleeding cannot be controlled. Reference #1: Withey S, Tamimi A. Spontaneous pulmonary haemorrhage into an existing emphysematous bulla. BMJ Case Reports. 2016 Reference #2: Bowler RP, Durham J, Schwarz MI. Massive hemoptysis from a pulmonary artery aneurysm associated with an emphysematous bulla. Chest. 1998;113(4):1130-1. Reference #3: Nakajima J, Yamamoto M, Kotsuka Y, et al. Hemoptysis from an emphysematous bulla developing after open-heart surgery: report of a case. Surg Today. 1997;27(3):266-8. DISCLOSURES: No relevant relationships by Sabin Bista, source=Web Response No relevant relationships by Deepak Chandra, source=Web Response no disclosure on file for Deepa Jayakrishnan; No relevant relationships by Navin Victor, source=Web Response

Durable Biventricular Support Using Right Atrial Placement of the HeartWare HVAD.

Patients with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels 1-2 who either have or are at risk for right ventricular failure face significant morbidity and mortality after continuous flow left ventricular assist device (CF-LVAD) implantation. Currently, the options for biventricular support are limited the Total Artificial Heart (TAH; CardioWest, Syncardia, Tuscon, AZ) or biventricular assist device (BiVAD), which uses bulky extracorporeal or implantable displacement pumps. We describe a successful series based on an innovative approach for biventricular support in consecutive INTERMACS levels 1-2 patients utilizing a HeartWare Ventricular Assist Device (HVAD; HeartWare, Framingham, MA) in a left ventricular (LV-HVAD) and a right atrial (RA-HVAD) configuration. From June 2014 through May 2016, 11 consecutive INTERMACS levels 1-2 patients with evidence of biventricular failure underwent implantation of a CF LVAD (10 LV-HVAD and 1 HeartMate II LVAD, Thoratec, Pleasanton, CA) and RA-HVAD pumps. A total of 4,314 BiVAD support days were accumulated in our case series. Seven patients have undergone orthotopic heart transplant, whereas 3 are ambulatory and are either waiting transplant or reconsideration for transplantation. There is one mortality in this case series, which was due to an intracranial bleed from supratherapeutic anticoagulation. Two other patients experienced hemorrhagic strokes, but without neurologic sequelae, whereas no patients have experienced ischemic strokes. There were two episodes of gastrointestinal bleeding. This is the largest series to date involving this approach with outcomes superior to those previously described in patients receiving biventricular support. We conclude this novel therapy is a viable alternative to current practices in the management of biventricular failure.

The effects of Ramadan fasting on patients with prosthetic heart valve taking warfarin for anticoagulation

IntroductionOral anticoagulation with warfarin is indicated for patients with prosthetic heart valves. The effects of religious fasting during Ramadan month (in the Islamic calendar) on anticoagulation aren’t clear. ObjectivesTo study the impact of Ramadan fasting on international normalized ratio (INR), quality of anticoagulation, dose of warfarin used and blood osmolarity. Methods18 patients were followed-up prospectively for 3months (pre- Ramadan, Ramadan and post-Ramadan months). Patients presented for weekly visits in which blood samples were obtained. ResultsNo significant difference in INR and warfarin dose was found between Ramadan month, and months before and after it. The post-Ramadan INR was significantly larger than pre-Ramadan (p=0.004). Blood osmolarity was significantly lower during Ramadan compared to pre- and post-Ramadan months. A significantly better quality of anticoagulation was noticed during Ramadan (p<0.001). A significantly larger ratio of supratherapeutic INR values occurred in the post-Ramadan month (p<0.05). A significantly larger ratio of infra-therapeutic INR values was noticed in the pre-Ramadan month (p<0.05). ConclusionNo significant difference in mean INR or warfarin dose was found and a better quality of anticoagulation was achieved during Ramadan. A tendency toward supra-therapeutic anticoagulation occurred after Ramadan, thus a closer follow up during this period may be reasonable.

Diagnostic and Therapeutic Yield of Endoscopy in Patients with Elevated INR and Gastrointestinal Bleeding

BackgroundGastrointestinal bleeding is a well-known risk of systemic anticoagulation. However, bleeding in the setting of supratherapeutic anticoagulation may have a milder natural history than unprovoked bleeding. It is a common clinical gestalt that endoscopy is common, but bleeding source identification or intervention is uncommon, yet few data exist to inform this clinical impression. Consequently, we sought to examine our institutional experience with gastrointestinal bleeding in the setting of supratherapeutic international normalized ratio (INR) with the aim of identifying predictors of endoscopically identifiable lesions, interventions, and outcomes. MethodsA retrospective review was conducted at a tertiary referral academic medical center to identify patients presenting with gastrointestinal bleeding in the setting of warfarin and a supratherapeutic INR (>3.5) who underwent an endoscopic procedure. Relevant clinical covariates, endoscopic findings, need for intervention, and outcomes were collected by review of the medical record. Logistic regression adjusting for potential confounders identified predictors of endoscopically significant lesions as well as intervention and outcomes. ResultsA total of 134 patients with INR 3.5 or greater (mean 5.5, range 3.5-17.1) presented with symptoms of gastrointestinal bleeding, most commonly as melena or symptomatic anemia. Antiplatelet agents were used by 54% of patients, and 60% of patients were on concomitant acid suppression on admission. Procedures included esophagogastroduodenoscopy (upper endoscopy; EGD) (n = 128), colonoscopy (n = 73), and video capsule endoscopy (n = 32). Active bleeding at first EGD or colonoscopy was found in only 19 patients (18%), with endoscopic intervention in only 26 patients (25%). At a critical threshold of INR 7.5 at presentation, the likelihood of finding an endoscopically significant lesion fell to <20%. On multivariate logistic regression, concomitant antiplatelet therapy (odds ratio [OR] 2.59; 95% confidence interval [CI], 1.13-5.94), timing of EGD within 12 hours of presentation (OR 3.71; 95% CI, 1.05-13.08), and INR level (OR 0.79; 95% CI, 0.64-0.98) were the only significant independent predictors of identifying a source of bleeding. A risk score incorporating these covariates performed modestly in identifying risk of significant finding on EGD (area under the curve 0.68). We found no association between identification of a significant lesion at EGD and future readmission for gastrointestinal bleeding. ConclusionThis study demonstrates that the relationship between INR elevation and identification of a bleeding source or endoscopic intervention at EGD are indeed antiparallel. Concomitant antiplatelet therapy increases the likelihood of bleeding source identification and intervention, as does EGD within 12 hours of presentation. However, regardless of source identification or endoscopic intervention, important clinical outcomes were unchanged, suggesting that decisions about endoscopy should be made on a case-by-case basis, particularly in patients with INR > 7.5. Future prospective studies on appropriate indications and timing of endoscopy in such patients are warranted.

Reversal of Trauma-Induced Bleeding and Anticoagulation with a Dabigatran-Specific Antidote (idarucizumab) As Assessed By Shed and Washed Blood Tests in a Pig Model of Supratherapeutic Anticoagulation and Trauma

Background: The most frequent side effect associated with anticoagulant therapy is bleeding. Testing reversal strategies in patients is difficult due to the unpredictability, rarity and heterogeneity of these events. Currently methods to reverse this bleeding are being tested in a variety of clinical settings in volunteers by using reversal of anticoagulation as a marker of reversal of bleeding in patients. However, the limitation of volunteer studies is the lack of understanding between the assay being used to measure anticoagulation and if its reversal has any relevance for bleeding reversal in patients. A marker of bleeding that was safe to use in volunteers and also relevant for predicting reversal of bleeding in a patient would be advantageous.Objective: The feasibility of two markers of bleeding - fibrin formation (fibrinopeptide A, FPA) in blood as it exits a wound and blood loss measured via a washed blood method, both at a superficial wound site - were tested in pigs under high dabigatran anticoagulation. Reversal of dabigatran anticoagulation and bleeding following trauma injury were evaluated with idarucizumab and outcomes compared to the markers of bleeding from superficial wound.Methods: After ethical approval dabigatran etexilate (30 mg/kg p.o. twice daily, n=24) or placebo (n=6, no dabigatran anticoagulation) was administered to male pigs for 3 days. On Day 4, the pigs were anesthetized and given a 90 min infusion of active dabigatran. A standardized blunt liver injury (0 min) was performed and animals underwent hemorrhagic shock, 15 min later were randomized to receive idarucizumab (30, 60 or 120 mg/kg) or vehicle. Blood loss was measured at defined time points over 4 hrs post injury. At the same time points a standardized cut was made on the inner side of the ear using an adult Surgicutt® device, one cut for each method. Shed blood was collected from the wound site as it emerged over 4 min, placed in protease inhibitor solution and processed for FPA measurement by ELISA. For washed blood method, blood as it exited the wound in 10 sec intervals was diluted in saline into 96 wells and measured photometrically. AUC over 15 min was recorded as blood loss. Blood samples were collected over time to measure active dabigatran by diluted thrombin time (dTT). Data shown as mean ± SE.Results: Cumulative blood loss was 630 ± 56 mL in the placebo group and 2977 ± 129 mL in the dabigatran-treated group. There was a dose-dependent reduction in blood loss by 47% (1586 ± 253 mL), 64% (1064 ± 40 mL) and 62% (1140 ± 44 mL) following treatment with 30, 60 and 120 mg/kg idarucizumab (p<0.001). Dabigatran plasma levels were 1228 ± 320 ng/mL prior to injury with no significant differences between groups. Dabigatran activity decreased within 5 min of idarucizumab administration, with a dose-dependent reduction over 240 min and was completely inhibited with 120 mg/kg.FPA in blood from the wound in dabigatran-treated groups was decreased ~74% vs non-anticoagulated group (211.2 ± 86 vs 53.7 ± 13 ng/mL). FPA increased by 2.6-fold (136.3 ± 96 ng/mL), 1.4-fold (103.9 ± 59 ng/mL) and 6.2-fold (251.9 ± 139 ng/mL) over baseline following 30, 60 and 120 mg/kg idarucizumab, respectively. At 240 min, FPA levels were 12%, 25% and 52% of non-anticoagulated animals with increasing idarucizumab doses and correlated with levels of dabigatran at 240 min.Washed blood loss (AUC) in dabigatran-treated animals was increased ~7-fold prior to injury vs non-anticoagulated groups (2110 ± 420 vs 309.1 ± 11.2 OD*sec). There was a dose-dependent reduction in washed blood loss by 2.5% (1682 ± 688 OD*sec), 48% (889 ± 304 OD*sec), and 79% (370 ± 97 OD*sec) 30 min following 30, 60 and 120 mg/kg idarucizumab vs dabigatran-treatment (1724 ± 298 OD*sec). Washed blood loss was comparable to the non-anticoagulated group (186 ± 59 vs 281 ± 201 OD*sec) with 120 mg/kg idarucizumab after 240 min, also correlating with lack of dabigatran anticoagulant activity.Conclusions: This study shows that bleeding and its reversal with a dabigatran-specific antidote can be evaluated using alternative methods that measure FPA levels in shed blood and washed blood loss at non-trauma superficial wound sites. The reversal of blood loss and FPA generation correlated with reversal of bleeding from a trauma wound. These methods may serve as potential markers in experimental bleeding and trauma models to sensitively assess blood loss and to also monitor reversal agents. DisclosuresGrottke:Boehringer Ingelheim : Consultancy, Research Funding; CSL Behring: Research Funding. Honickel:Boehringer Ingelheim : Travel support Other. Schurer:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. van Ryn:Boehringer Ingelheim Pharma: Employment.

Abstract 18544: Bloods Loss in Dabigatran Anticoagulated Pigs With Polytrauma is Significantly Reduced by Early Therapy With Activated and Non-activated Prothrombin Complex Concentrates

Introduction: The reversal of the new oral anticoagulants in severely bleeding patients with prothrombin complex concentrates remains uncertain with conflicting evidence. This study assessed the ability of a four-factor PCC and activated PCC (aPCC) to reverse dabigatran anticoagulation in a porcine polytrauma model. Methods: After ethical approval, male pigs (n=30) were given dabigatran etexilate for 3 days (30 mg/kg bid PO), the sham group (n=6) received placebo. To accomplish supratherapeutic anticoagulation, dabigatran was infused for 90 min (30 min: 0.77 mg/kg/h; 60 min 0.52 mg/kg/min) prior to injury on day 4 in anaesthetized pigs. A standardized blunt liver injury and bilateral femur fractures were induced. Following hemorrhagic shock, resuscitation was started 5 min after trauma and blood loss (BL) was recorded 12 min post trauma. Randomized animals (n=6/group) received a single injection of PCC or aPCC (25 and 50 IU/kg), or vehicle (control). BL and hemodynamic variables were monitored over 5 h or until time of death. Data were analyzed by ANOVA (± SD). Results: After infusion and prior to injury dabigatran levels were 559 ± 36 ng/mL and remained elevated throughout. In contrast to sham animals (BL: 601 ± 137 mL), BL in in all anticoagulated animals was significantly elevated 12 min post injury (BL : 791 ± 54 mL). Anticoagulation with dabigatran without PCC therapy resulted in a total BL of 3774 ± 628 mL) with 100% mortality (survival time: 65-146 min; p&lt;0.05 vs PCC/aPCC 50 IU/kg treated animals). Although the onset of bleeding was reduced in animals receiving 25 IU/kg PCC or aPCC, total BL (PCC: 3679 ± 782 mL; aPCC: 3638 ± 474 mL) was similar to control animals. In contrast, application of 50 IU/kg PCC (1767 ± 135 mL) or aPCC (1647 ± 302 mL) showed a significant reduction in total BL with 100% survival. Conclusions: This porcine model demonstrates that high doses of PCC and aPCC application of PCC may be a reasonable intervention for dabigatran-treated patients with life-threatening haemorrhage, though these data need clinical confirmation.

Supratherapeutic anticoagulation at presentation is associated with reduced mortality in nonvariceal upper gastrointestinal hemorrhage.

Introduction: Warfarin is a widely used and easily reversible anticoagulant. Although bleeding is more likely in warfarin users, it may also be more readily treated. This retrospective observational case-control study compares the outcome of acute nonvariceal upper gastrointestinal hemorrhage in warfarin users with a supratherapeutic international normalized ratio (INR) and outcome in non – warfarin users. Patients and methods: Clinical and endoscopic data for patients presenting with overt upper gastrointestinal hemorrhage were collected between 23rd February 2001 and 12 October 2010. Patients with variceal hemorrhage were excluded. Warfarin users with a supratherapeutic INR (≥ 3.0) at presentation (supratherapeutic anticoagulation [SA] group) were matched to a cohort with upper gastrointestinal hemorrhage not taking warfarin at presentation (control group). Patients were matched by age, sex, Rockall score, year of endoscopy, inpatient or outpatient status, and the presence of disseminated cancer at presentation. The incidence rates of major outcomes in the two groups were compared. Results: A total of 128 patients (SA group) were matched to 135 control patients. The SA group patients were less likely to die within 30 days (6.25 % vs. 15.5 %, odds ratio = 0.36, P = 0.028 by Test for Equality of Proportions). There was a trend toward more surgery in the control group (5 % vs. 2 %), and rates of blood transfusion (77 % vs. 70 %) were similar in the two groups. Conclusion: In patients presenting with nonvariceal upper gastrointestinal hemorrhage, a supratherapeutic INR at presentation due to warfarin use is associated with reduced mortality.

New oral pharmacotherapeutic agents for venous thromboprophylaxis after total hip arthroplasty.

Patients undergoing total hip arthroplasty (THA) are at high risk for developing venous thromboembolism and, therefore, require short term prophylaxis with antithrombotic agents. Recently, target specific oral anticoagulants (TSOA) including the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have been approved for THA thrombopropylaxis in various countries. The TSOAs provide a rapid acting, oral alternative to parenteral agents including low-molecular weight heparins (LMWH) and fondaparinux; and compared to warfarin, they do not require routine laboratory monitoring and possess much fewer drug-drug interactions. Based on phase III clinical studies, TSOAs have established themselves as an effective and safe option for thromboprophylaxis after THA compared to LMWH, particularly enoxaparin, but require additional evaluation in specific populations such as the renally impaired or elderly. The ability to monitor and reverse these TSOAs in the case of bleeding complications or suspected sub- or supra-therapeutic anticoagulation is of importance, but remains investigational. This review will focus on the drug-specific characteristics, efficacy, safety, and economic impact of the TSOAs for thromboprophylaxis following THA, as well as the aspects of therapeutic monitoring and anticoagulation reversal in the event of bleeding complications or a need for urgent reversal.

Colonic Dieulafoy's Lesion: A Rare Cause of Lower Gastrointestinal Hemorrhage and Review of Endoscopic Management.

Dieulafoy's lesions are a rare cause of gastrointestinal hemorrhage. Extragastric Dieulafoy's lesions are even more uncommon. We report the case of a 75-year-old woman who presented with gastrointestinal bleeding from a transverse colonic Dieulafoy's lesion. She presented with two episodes of melena followed by one episode of fresh blood per rectum. In addition, there was associated presyncope and anemia (hemoglobin 69 g/L) in the setting of supratherapeutic warfarin anticoagulation (INR 6.2) for nonvalvular atrial fibrillation. Esophagogastroduodenoscopy was negative for an upper GI source of bleeding but on colonoscopy an actively oozing Dieulafoy's lesion was identified in the transverse colon. Bipolar cautery and hemostatic endoclips were applied to achieve hemostasis. Clinicians should consider this rare entity as a potential cause of potentially life-threatening lower gastrointestinal bleeding and we review the endoscopic modalities effective for managing colonic Dieulafoy's lesions.