Life-threatening Bleeding Events Research Articles

Iliopsoas Hemorrhage in Pediatric Patients with Hemophilia, Experience from One Centre

Introduction: Iliopsoas hematoma is a serious, life threatening bleeding event in patients with hereditary clotting disorders and significantly associated with morbidity. It occurs most commonly in patients with severe hemophilia (Balkan et al Haemophilia 2005). In this review, we evaluated our patients with iliopsoas hematoma and compared with literature.Methods: The eleven pediatric patients with hemophilia and iliopsoas hematoma treated in a research and training hospital in Istanbul, between 2005 and 2015 were enrolled. The clinical characteristics including symptoms, signs, complications, and treatment were analyzed retrospectively.Results: We evaluated 14 episodes of iliopsoas hematoma from 11 patients (10 hemophilia A and 1 hemophilia B). All patients were male and the median age was 12 (8 -14) years old. Eight patients had one episode, three had two episodes. One patient had a high titer inhibitor against factor VIII. The hematoma was spontaneous and unilateral in all cases. The most common symptoms were hip pain and hip flexion contracture. Iliopsoas hematomas were confirmed by ultrasound, CT or MR scan. The treatment consisted of factor replacement and rehabilitation therapy. One patient needed erythrocytes transfusion. The mean duration of factor replacement therapy was 13.5 +/- 2.1 days. One severe hemophilia A patient with inhibitor treated with recombinant factor VIIa. Long term complications included paresthesia in 3 patients in the distribution of femoral nerve, quadriceps atrophy in 3 patients and permanent abnormal posture in one patient.Conclusion: The psoas muscles are located in the iliopsoas compartment posterior to the transversalis fascia, which is the posterior boundary of the retro peritoneum. Presentation of iliopsoas hematomas is often non-specific with abdominal, pelvic, back or groin pain or swelling. If they are large, iliopsoas hematomas can present with constipation, urinary frequency or fever. They can even compress the femoral nerve and cause a femoral neuropathy . A delay in treatment may result in permanent femoral nerve palsy (Mannucci N Engl J Med 2004). In this report, we present our experience and treatment modality in 14 episodes of iliopsoas hematoma in pediatric hemophilia patients. Rehabilitation treatment with factor replacement is safe and effective therapy for patients with small hematomas and little or no neurological symptoms. More aggressive recommendations have been made for patients with large hematomas and severe neurological symptoms or hemodynamic instability. An early diagnosis allows early factor replacement therapy, and decreases the risk of recurrence and morbidity. DisclosuresNo relevant conflicts of interest to declare.

Engineered Factor Xa Variants Retain Procoagulant Activity Independent of Direct Factor Xa-Inhibitors

The venom of the Australian Elapid snake Pseudonaja textilis contains a prothrombin-activating complex that consists of factor Xa (FXa) and factor Va (FVa) homologs which are evolutionary adapted to derail the hemostatic system of its prey, leading to runaway coagulation. These adaptations include functional resistance to inactivation by the main inhibitors of coagulation, antithrombin and activated protein C. Further studies revealed that venom FXa, unlike other FXa species, is also resistant to inhibition by direct oral FXa-inhibitors such as rivaroxaban and apixaban (Ki >1000 nM for venom FXa vs. 1 nM for human FXa). Accordingly, venom FXa is able to support thrombin generation (TG) in FX-depleted plasma spiked with pharmacological concentrations (0.4-2 μM) of these FXa-inhibitors. While human FXa-initiated TG resulted in a 8-fold prolonged lag time and a 70% reduced thrombin peak, those parameters were within normal range in venom FXa-triggered TG.Venom FX homologs produced by Elapid snakes comprise a heterogeneous insertion between His91-Tyr99 (chymotrypsin numbering) in the serine protease domain. A recent crystal structure of one of these homologs shows that this insertion is in close proximity of the active site pocket. In contrast, P. textilis liver-derived plasma FX, which, when activated, is fully inhibited by the FXa-inhibitors (Ki10 nM), lacks this structural feature. We investigated whether the His91-Tyr99 insertion is at the basis of the reduced sensitivity of venom FXa towards FXa-inhibitors. To do so, we constructed and stably expressed human-snake FX chimeras (FX-A, -B, -C) that incorporate His91-Tyr99 insertions from three venom FXa homologs. The chimeric FX variants were purified by successive ion-exchange and hydrophobic interaction chromatography steps, and FXa was generated following RVV-X-activation and size-exclusion chromatography.Evaluation of the kinetic parameters of prothrombin conversion in the presence of saturating amounts of FVa and anionic phospholipids revealed that the chimeric FXa variants exhibit an up to ~4-fold enhanced affinity for prothrombin (Km 0.11-0.29 μM) as compared to recombinant human FXa (rhFXa; Km 0.41 μM). The rate of prothrombin activation was 3-10-fold reduced (kcat 118-370 min-1 vs. 1243 min-1 for rhFXa), which may be indicative of a modified active site conformation. Consistent with this, the rate of chimeric FXa inhibition by antithrombin was impaired (kapp 0.12-0.95 x 103 M-1 s-1 vs. 4.07 x 103 M-1 s-1 for rhFXa). Furthermore, the variant that was most poorly inhibited by antithrombin (variant A) also exhibited the lowest catalytic rate of prothrombin conversion and vice versa (variant C). Conversely, apixaban or edoxaban inhibition of the FXa variants assembled into prothrombinase led to the highest Ki for chimeric variant C (2.3 or 0.3 µM), followed by variants B (1.4 or 0.2 µM), and A (0.2 or 0.006 µM) compared to rhFXa (0.004 or 0.0005 µM). Evaluation of the inhibition of uncomplexed FXa variants employing peptidyl substrate conversion revealed a similar decrease in sensitivity to the FXa-inhibitors (≤500-fold). These data suggest that insertion of the snake venom His91-Tyr99 regions indeed results in impaired engagement of the FXa active site pocket.We next assessed whether chimeric variant C, which is most resistant to inhibition by the direct FXa-inhibitors, is able to restore thrombin generation in a plasma system in the presence of apixaban or edoxaban. While rhFXa-triggered (5 nM) thrombin formation in FX-depleted plasma was inhibited by 2 μM apixaban, initiation with FXa-C (5 nM) resulted in normal thrombin generation parameters (peak thrombin 98%). In addition, the zymogen form of variant C also supported tissue factor-initiated (2 pM) thrombin generation in FX-depleted plasma with inhibitor concentrations up to 6 μM (apixaban) or 2 μM (edoxaban). Under these conditions, little if any thrombin was formed with rhFX present (peak thrombin 5%). We obtained similar results when performing these experiments in normal pooled plasma.Taken together, these results show that chimeric FX is able to restore hemostasis in plasma inhibited by the direct FXa-inhibitors, both in the zymogen as well as protease state. As such, these variants have the potential to serve as rescue therapeutic agents to overcome the effect of FXa-inhibitors in case of potential life-threatening bleeding events or emergency surgical interventions. DisclosuresBos:Bayer Hemophilia Awards: Research Funding.

Abstract 17392: Gastrointestinal Bleeding With Edoxaban versus Warfarin: Results From the ENGAGE AF-TIMI 48 Trial

Background: There is more major gastrointestinal bleeding (M-GIB) with most NOACs than with warfarin. The clinical impact of this finding is poorly understood. Methods: The ENGAGE AF-TIMI 48 trial compared the efficacy and safety of higher-dose (HD-E: 60 mg/ 30mg) or lower-dose (LD-E: 30 mg/15 mg) edoxaban regimens with dose-adjusted warfarin for prevention of stroke and systemic embolism in non-valvular atrial fibrillation. ISTH definitions for major and life-threatening (LT) bleeding events were utilized. In this pre-specified analysis, we investigated the adjudicated M-GIB events utilizing pre-defined severity and outcome endpoints. Results: Although the risk of M-GIB was higher with HD-E than with warfarin, the risk of LT or fatal GIB was similar (figure), and surgery for GIB was required less frequently with HD-E than warfarin (HR 0.37; 95%CI, 0.16-0.88; p=0.03). The risk for M-GIB-related permanent drug discontinuation was similar with HD-E and warfarin (HR 0.96; 95% CI, 0.67-1.37, p=0.8), as were the risks of hospitalization (HR 1.14; 95%CI, 0.92-1.40, p=0.2) and Hgb decrease > 5 g/dL (HR 1.01; 95%CI, 0.74-1.38; p=0.9). The risks of M-GIB and of LT or fatal GIB were lower with LD-E than with warfarin (Figure), as were the risks of M-GIB-related permanent drug discontinuation (HR 0.51; 95% CI, 0.33-0.78, p=0.002), hospitalization (HR 0.67; 95%CI, 0.53-0.85; p=0.001), Hgb decrease > 5 g/dL (HR 0.58; 95%CI, 0.40-0.84; p=0.003), and M-GIB requiring transfusion of > 2 units of red cells (HR 0.66; 95%CI, 0.50-0.89; p=0.006). Fatal GIB occurred in 2, 3 and 7 patients treated with HD-E, LD-E and warfarin, respectively. Conclusions: M-GIB and LT-GIB with edoxaban are dose-dependent. Although the risk of M-GIB is higher with HD-E than warfarin, the risk of LT-GIB or fatal GIB is similar and the severity and outcomes are no worse than with warfarin. The risks of M-GIB, and of LT-GIB or fatal GIB, are lower with LD-E than warfarin.

Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant.

Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life-threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3years among patients without bleeding was 67·1% for only 17·1% for patients with life-threatening bleeding (P<0·001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development.

Specific antidotes in development for reversal of novel anticoagulants: a review.

In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.

Rivaroxaban-Induced Nontraumatic Spinal Subdural Hematoma: An Uncommon Yet Life-Threatening Complication.

In the last decade, the desire for safer oral anticoagulants (OACs) led to the emergence of newer drugs. Available clinical trials demonstrated a lower risk of OACs-associated life-threatening bleeding events, including intracranial hemorrhage, compared to warfarin. Nontraumatic spinal hematoma is an uncommon yet life-threatening neurosurgical emergency that can be associated with the use of these agents. Rivaroxaban, one of the newly approved OACs, is a direct factor Xa inhibitor. To the best of our knowledge, to date, only two published cases report the incidence of rivaroxaban-induced nontraumatic spinal subdural hematoma (SSDH). Our case is the third one described and the first one to involve the cervicothoracic spine.

FEIBA™ for Reversal of Direct Oral Anticoagulant Associated Major Bleeding

▪Introduction: Direct oral anticoagulants (DOACs) are indicated for the prevention of systemic embolism in patients with atrial fibrillation and for the prevention and treatment of venous thrombosis. Although DOACs offer advantages over the vitamin K antagonists, some hesitancy remains over their use given the lack of specific antidotes for management of life threatening bleeding events. In vivo studies, case reports and case series have shown that prothrombin complex concentrate (PCC) and activated PCC might potentially be used to control life threatening bleeding in patients with DOAC-associated bleeding episodes. Herein we describe management and outcomes of DOAC-associated life threatening bleeding events using an activated PCC (FEIBA™).Methods: A retrospective review of patients presenting with DOAC-associated (dabigatran, rivaroxaban or apixaban) life threatening bleeding to The Ottawa Hospital between January 2013 and June 2014 are included. Patients received 25 – 50 units/kg of FEIBA™. The primary outcome was adverse thrombotic and embolic events during follow-up. Secondary outcome was symptomatic control of bleeding.Results: Nine patients presented to hospital with life threatening bleeding episodes (post trauma: n=3; spontaneous bleeding: n=6). Spontaneous episodes included epistaxis or gastro-intestinal bleeding. Baseline characteristics are depicted in Table 1. A majority of patients had atrial fibrillation (n=8) and received rivaroxaban (n=5).The last dose of DOAC was taken within 24 hours of bleeding events for all patients. All patients received supportive management, interventions/procedures aimed at attaining source control of bleeding when possible, and transfusion of FEIBA™ for reversal of anticoagulant effect. Adverse events after receiving FEIBA™ were uncommon with one patient experiencing a TIA with expressive aphasia and visual field deficit on the evening of FEIBA™ transfusion; deficits resolved by the time of hospital discharge. Two patients with GI bleeding continued to have ongoing bleeding despite FEIBA™ administration and two patients died as a result of major bleeding.Conclusions: In this cohort of patients with major bleeding associated with DOACs, FEIBA™ administration, in addition to supportive care, was helpful in minimizing further complications of most bleeding events and associated with a low rate of adverse events. Prospective studies are needed to evaluate benefits and harms of FEIBA™ for management of DOAC associated major bleeding.Abstract 1540. Table 1:Patients with Life-threatening BleedingPatient (Age and Gender)Indication for DOAC [AF(CHADS2); VTE]DOAC and DosageSite of BleedingIntervention/ProcedureUnits of PRBCs TransfusedAdditional TreatmentFEIBA™ Dose (IU)(1st/2nd)Adverse Events post-FEIBA™ AdministrationSurvived Hospitalization85 MaleAF (2)Rivaroxaban 20 mg dailyEpistaxisNasal Packing0–3275–Yes86 MaleAF (2)Rivaroxaban 20 mg dailyLGIBAngiogram, no embolization performed10Vitamin K3159/ 2952–Yes84 MaleAF (2)Dabigatran 110 mg BIDOrbital vitreous hemorrhageSurgical repair of ruptured globe0–1812–Yes92 MaleAF (6)Apixaban 5 mg BIDLeft handConservative management1Tranexamic acid2718TIAYes85 MaleVTERivaroxaban 20 mg dailyLGIBConservative management2Vitamin K1740–Yes90 FemaleAF (5)Rivaroxaban 20 mg dailySDHConservative management0–3275–No; died of major bleed93 FemaleAF (6)Apixaban 2.5 mg BIDLGIBConservative management4–2241–No93 MaleAF (3)Rivaroxaban 15 mg dailyUGIBUpper endoscopy, no intervention4Vitamin K3000–No; died of major bleed and septic shock81 MaleAF (4)Dabigatran 110 mg BIDLGIBUpper endoscopy and colonoscopy, no interventions4–3362–NoAF = atrial fibrillation; BID = twice daily; CHADS = congestive heart failure, hypertension, age, diabetes, stroke; DOAC = direct oral anticoagulant; IU = international units; LGIB = lower gastrointestinal bleeding; PRBC = packed red blood cells; SDH = subdural hematoma; TIA = transient ischemic attack; UGIB = upper gastrointestinal bleeding; VTE = venous thromboembolism DisclosuresOff Label Use: FEIBA is an activated prothrombin complex concentrate that was used during management of life threatening bleeding in patients with direct oral anticoagulant-associated bleeding episodes..

Impact of the Use of Transradial Versus Transfemoral Approach as Secondary Access in Transcatheter Aortic Valve Implantation Procedures

No data exist on the impact of vascular complications related to the secondary access site in transcatheter aortic valve implantation (TAVI). The objectives of this nonrandomized study were to determine the rate of vascular complications related to the secondary access site in TAVI procedures and to evaluate the clinical impact of using the radial versus femoral approach as a secondary access in such procedures. A total of 462 consecutive patients (mean age 79 ± 9 years, 50% men) who underwent TAVI were included. The femoral approach (FA) was used as the secondary access (for the insertion of a 5F pigtail catheter) in 335 patients and the radial approach (RA) in 127 patients. Thirty-day events were prospectively collected. There were no baseline differences between groups, except for a higher prevalence of women and peripheral disease in the FA group (p <0.05 for both). A total of 74 vascular access site complications occurred in 70 patients (15%), and 23% of them (29% in the FA group) were related to the secondary access. The use of FA as secondary access was associated with a higher rate of vascular complications (5.0% vs 0% in the RA group, p = 0.005, adjusted p = 0.014). All major vascular complications related to the secondary access occurred in the FA group (3% vs 0% in the RA group, p = 0.040, adjusted p = 0.049), and this translated into a higher rate of major and/or life-threatening bleeding events related to the secondary access in the FA group (3% vs 0% in the RA group, p = 0.040, adjusted p = 0.049). In conclusion, about 1/4 of vascular access site complications in TAVI are related to the secondary access. The use of the RA as a secondary access was associated with a major reduction in vascular complications. These results highlight the impact of secondary access vascular complications in TAVI procedures and support the use of the RA as the preferred secondary access.

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Introduction: Factor Xa inhibitors lack a commercially available antidote. Little information exists on the management of life threatening bleeding in the presence of factor Xa inhibitors. Methods: A PubMed search was performed for peer-reviewed journal articles describing animal or human subjects receiving direct factor Xa inhibitors with attempts to reverse the anti-coagulant effect with the non-specific reversal agents aPCC, PCC or rFVIIa. In addition, our pharmacy records were searched for the administration of any non-specific reversal agent to patients on any factor Xa inhibitor who presented with a life threatening bleed. Charts were assessed for documentation regarding cessation of bleeding, hemoglobin levels and coagulation labs. Results: Only 7 studies fit inclusion criteria. Five studies examined coagulation parameters in non-bleeding subjects; 1 was performed on healthy young men and showed reversal of a slightly prolonged INR with PCC administration. Two studies examined life threatening bleeding in animal models. One study found that mice given PCC, or rFVIIa, resulted in no improvement in PT prolongation, but did improve neurologic outcomes and decreased cerebral hematoma expansion. In contrast, the second study found PCC and rFVIIa partially corrected coagulation parameters but did not affect hepatosplenic blood loss in rabbits. Our case series found 3 patients with life threatening bleeds who were administered aPCC, which in all cases resulted in cessation of bleeding without further need for transfusions and no observed complications. Conclusions: Only 2 animal studies have examined the management of life threatening bleeding events related to factor Xa inhibitors with differing results. Our case series shows that aPCC is an effective reversal agent for patients with factor Xa inhibitor related life threatening bleeding events. Protocols need to be designed for management of life threatening bleeds in patients on factor Xa inhibitors.

Use Of Prothrombin Complex Concentrates In Warfarin Anticoagulation Reversal In The Emergency Department: A Quality Improvement Study Of Administration Delays

Introduction In some bleeding situations, quick reversal of warfarin anticoagulation is important. In the event of a major life-threatening bleeding event, the anticoagulation reversal delay can have an impact on mortality. This study aimed to improve the administration delay when using Prothrombin Complex Concentrate (PCC) for the emergent reversal of warfarin anticoagulation in the emergency department. Methods An audit and feedback quality improvement project was conducted in three phases: a retrospective audit phase, an analysis and feedback phase and prospective evaluation phase. The charts of all eligible patients in a single Emergency Department (ED) in Québec, Canada, who received 4-factor PCC since the introduction of this product in 2009 until October 31, 2011 were retrospectively audited with pre-planned evaluation criteria. The administration delay of PCC was calculated from the time of prescription to the time of administration. After this retrospective chart audit, we determined where improvements could be attained, gave feedback to the ED and the blood bank, and we created an action plan to ensure the timely administration of PCC. The action plan was then implemented in practice to reduce the administration delay. Finally, a six-month prospective evaluation study was conducted to determine if our action plan was followed and improved the administration delays. Results Seventy-seven charts were reviewed in the retrospective chart audit. The mean administration delay was 73.6 minutes (STD [34.1]) with a median of 70.0 minutes (25-75% IQR [45.0-95.0]). We found that this delay was principally due to the following barriers that prevented timely administration of PCCs: communication problems between the ED and the blood bank and reconstitution and delivery inefficiencies. In order to address these barriers, we developed an action plan that involved the following elements: a flowchart to remind all clinicians how to order PCCs and a new delivery method from the blood bank to the ED. During the 6 months following the implementation of our action plan, 39 patients received PCCs and the mean administration time decreased to 33.2 minutes (STD [14.2]) (p&lt;.0001) with a median of 30.0 minutes (25-75% IQR [24.3-38.8]). Conclusion This audit and feedback quality improvement project involving the development and the implementation of an action plan comprising of a flowchart and a new delivery process reduced the administration time of PCC by more than half. Future studies to measure the impact of implementing a similar audit and feedback process involving an action plan in other centers should be conducted before this type of improvement process is implemented on wider scale. Disclosures: No relevant conflicts of interest to declare.

Clinical Outcomes of the First 100 Transcatheter Aortic Valve Implant (TAVI) Procedures at Flinders Medical Centre (FMC) as Defined by the Valve Academic Research Consortium-2 Consensus (WARC)-2 Statement

Background:TAVI has beenwidely accepted as a potential life prolonging intervention for inoperable patients with severe aortic stenosis. FMCperformed its 100th TAVI procedure with the Edwards-Sapien valve in February 2012. Objective:Utilising the updated (VARC)-2 standardised endpoint definitions for TAVI procedures, we sought to adjudicate clinical outcomes for the first 100 cases. Methods: The FMC TAVI database with patient, procedural and follow up data was interrogated. Clinical outcomes assessment were based on the (VARC)-2 consensus document. Results: Sixty-seven percent of the population were male and median age was 85 years. Mean logistic Euroscore was 33.8%. There were 74 transfemoral procedures. Procedural, 30 day and one year all cause mortality was 1%, 4% and 14%, respectively. Both 30 days and one year all cause mortality rates were higher in the transapical route althoughnot significant (p= 0.28). Periprocedural myocardial infarction rate was 2%. A single nondisabling (mRS<4) stroke was observed. No life threatening bleeding events were noted while BARC criteria major and minor bleed was 2% and 5%, respectively. Stage 1 acute kidney injury (AKI) rate was 9% with no higher stage AKI.Major vascular complication ratewas 4%.One-month pacemaker implantation ratewas1%.83.8%patientsnoted an improvement of one or more NYHA functional class. Conclusion: The first 100 TAVI procedures at FMC have been successful with better survival and lower complication rates compared to the PARTNER B cohort with significant improvement in functional class.

Transcatheter aortic valve implantation and bleeding: incidence, predictors and prognosis

Peri-procedural bleeding complications are feared adverse events in patients undergoing transcatheter aortic valve implantation (TAVI). Little is known about the implications of peri-procedural bleeding on clinical outcome. In a prospective single-center registry of consecutive patients undergoing TAVI, we investigated incidence, predictors and clinical consequences of life-threatening and major bleeding as defined by the Valve Academic Research Consortium. Among 389 consecutive patients undergoing TAVI by a transfemoral (79.2%), transapical (19.6%) or trans-subclavian (1.3%) approach between July 2007 and October 2011, life-threatening or major peri-procedural bleeding events occurred in 64 (16.4%) and 125 patients (32.1%), respectively. Patients with peri-procedural bleeding events had a higher logistic EuroSCORE, more advanced renal disease, and were more symptomatic as assessed by New York Heart Association functional class at baseline as compared to patients with no bleeding. Life-threatening bleeding was associated with a higher all-cause (17.2 vs. 5.6 vs. 3.0%, p < 0.001) and cardiovascular mortality (10.9 vs. 5.6 vs. 2.5%, p = 0.02) at 30 days compared to patients with major bleeding or no bleeding. Multivariate analysis identified transapical access (OR 2.6, 95% CI 1.4-4.8; p = 0.002), glomerular filtration rate <30 ml/min (OR 2.3, 95% CI 1.1-4.7, p = 0.031), and diabetes (OR 1.8, 95% CI 1.001-3.2, p = 0.049) as independent predictors of life-threatening, peri-procedural bleeding. Life-threatening bleeding complications in patients undergoing TAVI are associated with increased mortality. Renal impairment, diabetes, and transapical approach were identified as independent risk factors for life-threatening bleeding events.

2-Year Results of CoreValve Implantation Through the Subclavian Access: A Propensity-Matched Comparison With the Femoral Access

The goal of this study was to assess the procedural and 2-year results of the subclavian approach for transcatheter aortic valve implantation (TAVI) compared with those of the femoral approach by using propensity-matched analysis. The subclavian approach with the CoreValve prosthesis (Medtronic, Inc., Minneapolis, Minnesota) represents an interesting opportunity when the femoral access is unfeasible. All consecutive patients enrolled in the Italian CoreValve Registry who underwent TAVI with the subclavian approach were included. Propensity score analysis was used to identify a matching group of patients undergoing femoral TAVI. Subclavian approach was used in 141 patients (61% men; median age 83 years; median logistic European System for Cardiac Operative Risk Evaluation score 23.7%). The femoral group of 141 patients was matched for baseline clinical characteristics, except for peripheral artery disease. The 2 groups showed similar procedural success (97.9% vs. 96.5%; p = 0.47), major vascular complications (5.0% vs. 7.8%; p = 0.33), life-threatening bleeding events (7.8% vs. 5.7%; p = 0.48), and combined safety endpoint (19.9% vs. 25.5%; p = 0.26). The subclavian group showed lower rates of acute kidney injury/stage 3 (4.3% vs. 9.9%; p = 0.02), of minor vascular complications at the 18-F sheath insertion site (2.1% vs. 11.3%; p = 0.003), and of all types of bleeding events related to vascular complications. Survival at 2 years was 74.0 ± 4.0% in the subclavian group compared with 73.7 ± 3.9% in the femoral group (p = 0.78). The 2-year freedom from cardiovascular death was 87.2 ± 3.1% versus 88.7 ± 2.8% in the subclavian versus femoral group, respectively (p = 0.84). The subclavian approach for TAVI is safe and feasible, with procedural and medium-term results similar to the femoral approach. Subclavian access should be considered a valid option not only when the femoral approach is impossible but also when it is difficult, albeit feasible.

Blutungsrisiko und Blutungsnotfälle unter Rivaroxaban

SummaryRivaroxaban, the first direct factor-Xa inhibitor anticoagulant, has been approved for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery, for stroke prophylaxis in patients with non-valvular atrial fibrillation and for the treatment of deep vein thrombosis. There is no requirement for coagulation monitoring with rivaroxaban in routine clinical practice. However, in certain clinical circumstances such as life-threatening bleeding or an emergency operation the measurement of the thromboplastin time with a sensitive reagent will deliver first information. A quantitative determination of rivaroxaban plasma concentration is possible using an anti-factor Xa assay.In the case of a patient under long-term anticoagulation with rivaroxaban requiring an elective surgery, a discontinuation of rivaroxaban 20 to 30 hours before the operation is sufficient to normalize the associated bleeding risk, as long as the renal and liver function is normal. A longer interval should be taken into consideration, when the patient presents a renal and liver impairment or is of a higher age. In the event of an emergency operation effective rivaroxaban concentrations might be present. Nevertheless, we advise against using a prophylactic dose of factor concentrates. Recommendations: From a clinical perspective, in the event of a minor bleeding we recommend a temporary discontinuation of rivaroxaban, whereas for clinically relevant major or severe bleeding events a mechanical compression or a limited surgical i. e. interventional treatment is required. Supportive measures such as the administration of blood products or tranexamic acid might be beneficial. In addition to haemodynamic supportive measures life threatening bleeding events demand a comprehensive haemostasis management, as well as the application of PCC.

Periprocedural and Short-Term Outcomes of Transfemoral Transcatheter Aortic Valve Implantation With the Sapien XT as Compared With the Edwards Sapien Valve

The aim of this study was to analyze the short-term outcomes after transcatheter aortic valve implantation with the Edwards Sapien THV (ESV), compared with the Sapien XT THV (SXT) (Edwards Lifesciences, Irvine, California). The SXT has been recently commercialized in Europe, but there are no studies analyzing the efficacy and safety of SXT, compared with ESV. All consecutive patients (n = 120) who underwent transcatheter aortic valve implantation in our center via the transfemoral approach with either ESV (n = 66) or SXT (n = 54). Valve Academic Research Consortium endpoints were used. Mean age was 80 ± 8 years, and mean Logistic-European System for Cardiac Operative Risk Evaluation was 24.9 ± 17.0. The ilio-femoral artery minimal lumen diameter was smaller in patients treated with the SXT (7.27 ± 1.09 mm vs. 7.94 ± 1.08 mm, p = 0.002). Device success was high in both groups (96.3% vs. 92.4%, p = 0.45). Major vascular events were 3-fold lower in the SXT group (11.1% vs. 33.3%, relative risk: 0.40, 95% confidence interval: 0.28 to 0.57; p = 0.004). Life-threatening and major bleeding events were not significantly different between groups (18.5% vs. 27.3% and 35.2% vs. 40.9%, respectively). The SXT group had a lower 30-day Valve Academic Research Consortium combined safety endpoint (20.4% vs. 45.5%; relative risk: 0.44, 95% confidence interval: 0.24 to 0.80; p = 0.004). The 30-day mortality was 1.7% (n = 2). At 30 days, mean transaortic gradient was approximately 10 mm Hg in both groups and the aortic regurgitation was mild-to-moderate in 70.2% of SXT and 76.3% of ESV. The new SXT valve has the same short-term performance as the ESV but seems to be associated with a lower risk of major vascular complications and thus has a broader clinical application.

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1-VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1-VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*2-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C9*2*2-VKORC1AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB, an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA, alleles associated with moderate and high warfarin sensitivity, respectively.

Segmental Hemangioma of Infancy Complicated by Life‐Threatening Arterial Bleed

Infantile hemangiomas (IHs) are the most common benign vascular tumors of childhood. IH of "segmental" morphology, are clusters of hemangiomas with a configuration involving a broad anatomic territory of skin. They are the least common of all types and generally larger than regular hemangiomas, morphologically characterized as plaque-like lesions. Head and neck segmental hemangiomas have a higher risk of causing life-threatening complications and of having associated structural anomalies, i.e., PHACES syndrome (Posterior fossa malformations, hemangiomas, arterial anomalies, coartation of the aorta and other cardiac defects, eye abnormalities and sternal clefting or supra abdominal raphe). We present a patient with a segmental IH over the right anterior neck complicated by ulceration and life threatening arterial bleeding. Although segmental hemangiomas of head and neck have high incidence of ulceration, fortunately life threatening bleeding events are rare with only 7 previously recorded cases. We recommend that large, neck IH be followed closely for evidence of ulceration and that MRI/MRA be performed to adequately assess their vascular supply. Direct extension of the ulceration into arterial vessels is a possibility and can lead to severe bleeding. Life-threatening bleeding is an unusual complication of IH and may represents a surgical emergency. In such cases we recommend a multidisciplinary approach to their treatment.

Antihemophilic factor (recombinant) plasma/albumin-free method for the management and prevention of bleeding episodes in patients with hemophilia A

Hemophilia is a rare genetic bleeding disorder that, if not adequately controlled, is associated with life-threatening bleeding events and serious and costly complications, primarily from joint damage. The advent of effective clotting factor replacement therapy for patients with hemophilia is considered one of the foremost medical advances of the 20th century. The last 3 decades of experience in hemophilia care have witnessed the effectiveness of the care of patients with hemophilia within specialized comprehensive care centers, advances in factor replacement therapies, the benefits of prophylaxis over on-demand replacement therapy, and the role of aggressive management of joint disease to prevent dysfunction. Ongoing challenges, including the management of inhibitors to factor therapies and the consequences of thousands of patients with hemophilia becoming infected with human immunodeficiency virus and hepatitis C virus in the 1980s from contaminated plasma-derived factor concentrates, have highlighted the need for vigilance with respect to clotting factor product safety, access to care, and a full complement of choice of factor replacement therapies. Advate((R)) (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM]) is the first recombinant factor VIII therapy manufactured without human or animal protein additives to eliminate the risk of pathogen transmission that could be carried by these additives. Preclinical studies established bioequivalence with recombinant antihemophilic factor (Recombinate((R))), a product with 16 years of clinical experience. Currently licensed in 44 countries worldwide, rAHF-PFM has over 7 years of clinical research within 5 global studies supporting its safety and efficacy in the treatment of patients with hemophilia A.

Antihemophilic factor (recombinant) plasma/albumin-free method for the management and prevention of bleeding episodes in patients with hemophilia A

Antihemophilic factor (recombinant) plasma/albumin-free method for the management and prevention of leeding episodes in patients with hemophilia Steven PipeDepartment of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USAAbstract: Hemophilia is a rare genetic bleeding disorder that, if not adequately controlled, is associated with life-threatening bleeding events and serious and costly complications, primarily from joint damage. The advent of effective clotting factor replacement therapy for patients with hemophilia is considered one of the foremost medical advances of the 20th century. The last 3 decades of experience in hemophilia care have witnessed the effectiveness of the care of patients with hemophilia within specialized comprehensive care centers, advances in factor replacement therapies, the benefits of prophylaxis over on-demand replacement therapy, and the role of aggressive management of joint disease to prevent dysfunction. Ongoing challenges, including the management of inhibitors to factor therapies and the consequences of thousands of patients with hemophilia becoming infected with human immunodefi ciency virus and hepatitis C virus in the 1980s from contaminated plasma-derived factor concentrates, have highlighted the need for vigilance with respect to clotting factor product safety, access to care, and a full complement of choice of factor replacement therapies. Advate® (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM]) is the first recombinant factor VIII therapy manufactured without human or animal protein additives to eliminate the risk of pathogen transmission that could be carried by these additives. Preclinical studies established bioequivalence with recombinant antihemophilic factor (Recombinate®), a product with 16 years of clinical experience. Currently licensed in 44 countries worldwide, rAHF-PFM has over 7 years of clinical research within 5 global studies supporting its safety and efficacy in the treatment of patients with hemophilia A.Keywords: factor VIII, hemophilia A, recombinant proteins, clinical trials

Myocardial infarction: contemporary management strategies

Myocardial infarction (MI) is a common clinical diagnosis, associated with significant morbidity and mortality, not only in the short term, but also years following the index event. A more complete understanding of the pathophysiology of MI has ushered the era of multipronged treatment approach, with a combination of goal-directed revascularization, a broad adjunctive pharmacological therapy and aggressive secondary prevention measures. The goals of this article are to review the basic pathophysiological processes, which lead up to a clinical diagnosis of MI, to highlight the essential elements of clinical presentation and to summarize the evidence for comprehensive therapy. Emphasis has been placed on the choice of primary reperfusion therapy for ST-elevation MI, on risk-stratification of patients with non-ST elevation MI, and on rationale behind the selection of anti-ischaemic and antithrombotic therapy. Finally, evidence-based approach to secondary prevention is outlined.