Amanda Jane Zatta

CXCR4 Antagonism Attenuates the Cardiorenal Consequences of Mineralocorticoid Excess

Background— Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role. Methods and Results— We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg per day for 6 weeks through minipump) in dexoycorticosterone acetate (DOCA)-treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension, and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition. Conclusions— Taken together, these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation, and cardiorenal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease.

Use of Recombinant Factor VIIa in Patients with Amniotic Fluid Embolism A Systematic Review of Case Reports

BACKGROUNDnPatients with amniotic fluid embolism (AFE) (major cardiac and pulmonary symptoms plus consumptive coagulopathy) have high circulating tissue factor concentrations. Recombinant factor VIIa (rVIIa) has been used to treat hemorrhage in AFE patients even though rVIIa can combine with circulating tissue factor and form intravascular clots. A systematic review was done of case reports from 2003 to 2009 of AFE patients with massive hemorrhage who were and were not treated with rVIIa to assess the thrombotic complication risk.nnnMETHODSnMEDLINE was searched for case reports of AFE patients receiving rVIIa (rVIIa cases) and of AFE patients who received surgery to control bleeding but no rVIIa (cohorts who did not receive rVIIa). Additional AFE case reports were obtained from the Food and Drug Administration, the Australian and New Zealand Haemostasis Registry, and scientific meeting abstracts. The risk of a negative outcome (permanent disability or death) in rVIIa cases versus cohorts who did not receive rVIIa was calculated using risk ratio and 95% confidence interval.nnnRESULTSnSixteen rVIIa cases and 28 cohorts were identified who did not receive rVIIa. All patients had surgery to control bleeding. Death, permanent disability, and full recovery occurred in 8, 6, and 2 rVIIa cases and 7, 4, and 17 cohorts who did not receive rVIIa (risk ratio 2.2, 95% CI 1.4-3.7 for death or permanent disability vs. full recovery).nnnCONCLUSIONnRecombinant factor VIIa cases had significantly worse outcomes than cohorts who did not receive rVIIa. It is recommended that rVIIa be used in AFE patients only when the hemorrhage cannot be stopped by massive blood component replacement.

Elucidating the clinical characteristics of patients captured using different definitions of massive transfusion

The type and clinical characteristics of patients identified with commonly used definitions of massive transfusion (MT) are largely unknown. The objective of this study was to define the clinical characteristics of patients meeting different definitions of MT for the purpose of patient recruitment in observational studies.

Off-Label Use of Recombinant Factor VIIa in Pediatric Patients

OBJECTIVE: To examine off-label recombinant factor VIIa (rFVIIa) use in pediatric patients including clinical indications, dose, adverse events, and outcomes. METHODS: All pediatric patients entered into the Haemostasis Registry from 75 participating hospitals were analyzed. RESULTS: Three hundred and eighty-eight pediatric patients received off-label rFVIIa from 2003 to 2009. Median age was 12 months (interquartile range 1 month to 11 years). Clinical context included cardiac surgery (52.1%), medical (11.6%), other surgery (10.8%), hematology/oncology (10.3%), trauma (9.3%), intracranial hemorrhage (3.1%), and liver disease (2.8%). Twenty-six patients received extracorporeal membrane oxygenation at the time of rFVIIa administration. Median first dose was 114 μg/kg (interquartile range 90–181; range 7–2250). Thirty-four percent received >1 dose. There was a reduction in usage of red blood cells, platelets, fresh-frozen plasma, and cryoprecipitate in the 24 hours after the first dose for all patients (all P values < .001). Thromboembolic adverse events (TEAs) were reported in 5.4%. No association between TEA and size of first dose was found. Where data were available, 82% of patients were subjectively classified as responding to rFVIIa. Overall 28-day mortality was 27%. In multivariate analysis, pH values before administration and clinical context were independently associated with response to first dose and 28-day mortality. CONCLUSIONS: There was a significant reduction in blood product administration after rFVIIa and a subjective response rate of 82%. Both pH and clinical context were associated with response to rFVIIa and mortality. Overall, 5.4% had a TEA reported.

Effectiveness of massive transfusion protocols on mortality in trauma: a systematic review and meta-analysis

The effectiveness of massive transfusion protocols (MTPs) has been assumed from low quality studies with multiple biases. This review aimed to (i) evaluate the association between the institution of an MTP and mortality and (ii) determine the effect of MTPs on transfusion practice post trauma.

The Australian and New Zealand Haemostasis Registry: ten years of data on off-licence use of recombinant activated factor VII.

BACKGROUNDnRecombinant activated factor VII (rFVIIa) has been widely used as an off-licence pan-haemostatic agent in patients with critical bleeding. However, outside the trauma setting, there is relatively little high quality evidence on the risks and benefits of this agent. The Haemostasis Registry was established to investigate the extent of use, dosing, safety and outcomes of patients after off-licence rFVIIa treatment of critical bleeding.nnnMATERIALS AND METHODSnThe Registry recruited non-haemophiliac patients treated with rFVIIa from 2000-2009 (inclusive) in Australia and New Zealand. Detailed information was gathered on patients demographics, context of bleeding, rFVIIa administration, laboratory results, blood component and other therapies, and outcomes. Outcome measures included subjectively assessed effect of rFVIIa on bleeding (response), adverse events (thromboembolic and other) and 28-day mortality.nnnRESULTSnThe registry included 3,446 cases in 3,322 patients (median [IQR] age 56 [33-70] years, 65% (n=2,147) male). Clinical indications included cardiac surgery (45%), other surgery (18%), trauma (13%), medical bleeding (6%), liver disease (6%), and obstetric haemorrhage (5%). The median [IQR] dose was 91 [72-103] μg/kg and 77% received a single dose. Reduction or cessation of bleeding was reported in 74% and 28-day survival was 71% but outcomes varied depending on clinical context. pH strongly correlated with outcome measures; 81% of patients with pH <7.1 died. Approximately 11% of patients had thromboembolic adverse events. In multivariate analysis, pH prior to administration and bleeding context were independently associated with reported response to rFVIIa and 28-day mortality.nnnDISCUSSIONnThe Haemostasis Registry is the largest dataset of its kind and provides observational data on the off-licence use of rFVIIa over a 10-year period. It has been an invaluable resource for rigorously tracking adverse events and helping to inform clinical practice.

Uncontrolled Bleeding in Surgical Patients: The Role of Recombinant Activated Factor VIIa

Recombinant activated factor VII (rFVIIa), developed and effective in managing inhibitors in haemophilia patients, is being widely used off-label as a panhaemostatic agent with ongoing controversy as to its benefits and risks in terms of controlling critical haemorrhage and improving patient outcomes. Current insights into haemostatic mechanisms have resulted in a better understanding of the central role of FVII/FVIIa and tissue factor in the localization and initiation of haemostasis. There is a plethora of case reports and series published on the use of rFVIIa in critical life-threatening haemorrhage and in perioperative settings associated with significant blood loss or the potential for catastrophic haemorrhage. Additionally, the literature is replete with reviews for the use of rFVIIa in various clinical settings, but there is a dearth of good evidence from randomized controlled trials for efficacy. Safety, especially from the thrombogenicity perspective, has been a major issue, but turns out to be less of a concern with thrombotic potential needing to be weighed against the anticipated benefits. Although there is some clinical trial and observational data supporting efficacy it has been difficult to recommend clear clinical practice guidelines, especially as clinical outcome data in terms of morbidity and mortality is limited. Some of the best evidence relates to reduction in allogeneic blood transfusion requirements. This in itself is important and probably clinically relevant in view of the accumulating evidence that allogeneic blood transfusion is an independent risk factor for poorer clinical outcome. It is unlikely that there will be adequate randomized clinical trials to better answer the question of efficacy, thus making data from registries of greater importance. Indeed, the process of establishing efficacy, safety and regulation of a therapeutic that is increasingly used off-label is not without significant difficulties.

Use of recombinant activated factor VII in Jehovah's Witness patients with critical bleeding

The Australian and New Zealand Haemostasis Registry (ANZHR) included patients who received off‐licence recombinant activated factor VII (rFVIIa) for critical bleeding from 2000 to 2009. Approximately 1.3% of the ANZHR patients were Jehovahs Witnesses (JWs). We compared them with the non‐JW patients in the registry.

Evaluation of clinical coding data to determine causes of critical bleeding in patients receiving massive transfusion: a bi-national, multicentre, cross-sectional study

To evaluate the use of routinely collected data to determine the cause(s) of critical bleeding in patients who receive massive transfusion (MT).

Lethal Myocardial Reperfusion Injury

Early coronary artery reperfusion reduces infarct size and mortality and improves left ventricular contractile performance after myocardial ischemia compared to permanent occlusion. However, reperfusion itself causes either an acceleration of injury that is not present during ischemia or causes de novo reversible and lethal injury to heart tissue. In vitro and in vivo experimental data strongly suggest that reperfusion injury is initiated during the first few moments of reperfusion and proceeds over minutes to hours in a cascade involving numerous interactive mechanisms leading to damage or death of myocardium and coronary vascular endothelium. This reperfusion injury contributes to contractile dysfunction, metabolic derangements, and ultimately cell death by necrosis, apoptosis, and autophagy. The mechanisms underlying lethal reperfusion injury include: (1) generation of ROS (oxygen paradox) from mitochondria, cytosolic and extracellular compartments, coronary vascular endothelium, and inflammatory cells such as neutrophils in a robust burst followed by sustained increased levels; (2) intracellular calcium accumulation (calcium paradox); (3) rapid normalization of tissue pH (pH paradox); (4) activation of proteolytic enzymes; (5) opening of the mitochondrial permeability transition pore; and (6) an inflammatory-like response. Although inflammatory cells and other cell types involved in inflammation (e.g., endothelium) contribute ROS and proinflammatory mediators during reperfusion, the role of inflammation in lethal reperfusion injury remains incompletely understood. ROS and calcium accumulation and rapid normalization of tissue pH which occur during the early moments of reperfusion create an environment in which the mitochondrial permeability transition pore opens, thereby promoting mitochondrial swelling and the release of proapoptotic substances which directs the cell to pursue a necrotic or an apoptotic pathway to death. Microvascular obliteration, a major physiological consequence of ischemia-reperfusion injury, may lead to no-reflow zones of myocardium and may also be involved in expansion of infarction as the duration of reperfusion increases and no-reflow zones expand. Age and gender may affect the heart’s tolerance to ischemia such that lethal injury is more severe or occurs after shorter periods of ischemia; some mechanisms of reperfusion injury may be more exaggerated in older animal models but is known to occur in humans. Comorbidities such as hypertension, hypercholesterolemia, and diabetes may also exaggerate the response to ischemia-reperfusion by mechanisms that are relevant to reperfusion such as increased oxidant stress at reflow, preexisting endothelial cell dysfunction that limits the bioavailability of nitric oxide ((N{O}^{•})), or downregulation of the endogenous cardioprotective signaling pathways. Endogenous mechanisms exist that may combat reperfusion injury, such as the antioxidants glutathione and glutathione peroxidase, the autacoid adenosine, NO, and certain kinases (reperfusion injury salvage kinases, RISK). However, these are either not sufficiently stimulated or are rapidly overwhelmed. They can be enhanced by mechanical maneuvers such as postconditioning (a series of brief ischemia and reperfusion applied at the onset of reperfusion) or by pharmacological agents administered at the onset of reperfusion. Fully understanding the time course of reperfusion injury will help define and bracket the timing of effective reperfusion interventions. More fully understanding the mechanisms of reperfusion injury will help identify potential candidate therapies. Although previous clinical trials of drugs administered after percutaneous coronary interventions have revealed largely negative or inconclusive results, contemporary large-scale clinical trials should be undertaken with the immediacy and narrow window of reperfusion injury in mind, with the knowledge of effective concentrations of drugs at the target organ with consideration given to direct delivery to the target, and with appropriate duration of treatment to address immediate and delayed reperfusion injury.