Amanda K. Davis

Extracorporeal Membrane Oxygenation—Hemostatic Complications

The use of extracorporeal membrane oxygenation (ECMO) support for cardiac and respiratory failure has increased in recent years. Improvements in ECMO oxygenator and pump technologies have aided this increase in utilization. Additionally, reports of successful outcomes in supporting patients with respiratory failure during the 2009 H1N1 pandemic and reports of ECMO during cardiopulmonary resuscitation have led to increased uptake of ECMO. Patients requiring ECMO are a heterogenous group of critically ill patients with cardiac and respiratory failure. Bleeding and thrombotic complications remain a leading cause of morbidity and mortality in patients on ECMO. In this review, we describe the mechanisms and management of hemostatic, thrombotic and hemolytic complications during ECMO support.

Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels.

Ligand-induced ectodomain shedding of glycoprotein VI (GPVI) is a metalloproteinase-dependent event. We examined whether shear force, in the absence of GPVI ligand, was sufficient to induce shedding of GPVI. Human-citrated platelet-rich plasma or washed platelets were subjected to increasing shear rates in a cone-plate viscometer, and levels of intact and cleaved GPVI were examined by Western blot and ELISA. Pathophysiologic shear rates (3000-10 000 seconds(-1)) induced platelet aggregation and metalloproteinase-dependent appearance of soluble GPVI ectodomain, and GPVI platelet remnant. Shedding of GPVI continued after transient exposure to shear. Blockade of α(IIb)β(3), GPIbα, or intracellular signaling inhibited shear-induced platelet aggregation but minimally affected shear-induced shedding of GPVI. Shear-induced GPVI shedding also occurred in platelet-rich plasma or washed platelets isolated from a von Willebrand disease type 3 patient with no detectable VWF, implying that shear-induced activation of platelet metalloproteinases can occur in the absence of GPVI and GPIbα ligands. Significantly elevated levels of sGPVI were observed in 10 patients with stable angina pectoris, with well-defined single vessel coronary artery disease and mean intracoronary shear estimates at 2935 seconds(-1) (peak shear, 19 224 seconds(-1)). Loss of GPVI in platelets exposed to shear has potential implications for the stability of a forming thrombus at arterial shear rates.

ITAM receptor-mediated generation of reactive oxygen species in human platelets occurs via Syk-dependent and Syk-independent pathways

Background: Ligation of the platelet‐specific collagen receptor, GPVI/FcRγ, causes rapid, transient disulfide‐dependent homodimerization, and the production of intracellular reactive oxygen species (ROS) generated by the NADPH oxidase, linked to GPVI via TRAF4. Objectives: The aim of this study was to evaluate the role of early signaling events in ROS generation following engagement of either GPVI/FcRγ or a second immunoreceptor tyrosine‐based activation motif (ITAM)‐containing receptor on platelets, FcγRIIa. Methods and Results: Using an H2DCF‐DA‐based flow cytometric assay to measure intracellular ROS, we show that treatment of platelets with either the GPVI agonists, collagen‐related peptide (CRP) or convulxin (Cvx), or the FcγRIIa agonist 14A2, increased intraplatelet ROS; other platelet agonists such as ADP and TRAP did not. Basal ROS in platelet‐rich plasma from 14 healthy donors displayed little inter‐individual variability. CRP, Cvx or 14A2 induced an initial burst of ROS within 2 min followed by additional ROS reaching a plateau after 15–20 min. The Syk inhibitor BAY61‐3606, which blocks ITAM‐dependent signaling, had no effect on the initial ROS burst, but completely inhibited the second phase. Conclusions: Together, these results show for the first time that ROS generation downstream of GPVI or FcγRIIa consists of two distinct phases: an initial Syk‐independent burst followed by additional Syk‐dependent generation.

Evolving experience of treating antibody-mediated rejection following lung transplantation.

BACKGROUND The importance of antibody-mediated rejection (AMR) following lung transplantation remains contentious. In particular, the diagnostic criteria suggested to define AMR, namely the presence of donor-specific antibodies (DSA), C4d immunoreactivity, histological features and allograft dysfunction are not always readily applicable or confirmatory in lung transplantation. METHODS In a retrospective single-center study of 255 lung transplant recipients (LTR), we identified 9 patients in whom a clinical diagnosis of AMR was made within 12months of transplant, and define the immunological, histological, clinical features, as well as the therapeutic response of this cohort. RESULTS Nine LTR with AMR underwent combination therapy with high-dose intravenous corticosteroid, intravenous immunoglobulin, plasmapheresis and rituximab. Following therapy, while the total number of the original DSA dropped by 17%, and the median value of the mean fluorescence intensity (mfi) of the originally observed DSA decreased from 5292 (IQR 1319-12,754) to 2409 (IQR 920-6825) (p<0.001), clinical outcomes were variable with a number of patients progressing to either chronic lung allograft dysfunction or death within 12month. CONCLUSION AMR in lung transplantation remains both a diagnostic and therapeutic challenge, but when clinically suspected is associated with a variable response to therapy and poor long-term outcomes.

Prospective comparison of point-of-care international normalised ratio measurement versus plasma international normalised ratio for acute traumatic coagulopathy

Objective: Early detection of acute traumatic coagulopathy (ATC) might be useful to guide trauma resuscitation. This study aimed to compare results from a point‐of‐care (POC) international normalised ratio (INR) measuring device with plasma INR in acute trauma patients.

Low adhesion receptor levels on circulating platelets in patients with lymphoproliferative diseases before receiving Navitoclax (ABT-263)

To the editor: Leukemia cells express high levels of Bcl-2[1][1] and BH3 mimetics that antagonize the prosurvival function of Bcl-2 and related proteins, thereby inducing apoptosis, are useful treatments for patients with chemotherapy-refractory leukemia.[2][2] BH3 mimetics such as ABT-737 and ABT-

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI.

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk.

The evolving role of the transfusion practitioner.

Much of the recent work in transfusion practice has shifted to focus on the patient, after efforts over previous decades to ensure the quality and safety of blood products. After the commencement of hemovigilance and transfusion practice improvement programs, the introduction of transfusion practitioners (TP) into health care services and blood centers has continued to increase worldwide. Since this relatively new role was introduced, much work of the TP has focused on patient and staff education, adverse events, transfusion governance, and monitoring of transfusion practices within organizations. The complex nature of the transfusion process makes the TP an integral link in the transfusion chain. Together with hospital transfusion teams and committees, the TP works collaboratively to facilitate the transfusion change management programs and initiatives. Recently, the TP role has evolved to include an emphasis on patient blood management and, to some extent, is shaped by national standards and regulations. These established roles of the TP, together with the ever-changing field of transfusion medicine, provide new opportunities and challenges for a role that is continuing to evolve worldwide.

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

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

A Guide to Performing Cardiac Surgery in Patients with Hereditary Bleeding Disorders

This study presents the experience of a large Australian hospital in performing cardiac surgery on patients with hereditary bleeding disorders (HBDs) and provides a suggested approach for their perioperative management.