Association of Radial Artery Access with Reduced Incidence of Acute Kidney Injury.

Objectives: To determine if radial artery (RA) access compared with femoral artery (FA) access for percutaneous coronary intervention (PCI) is associated with a lower incidence of acute kidney injury (AKI). Background: AKI results in substantial morbidity and cost following PCI. Prior studies comparing the occurrence of AKI associated with radial artery (RA) versus femoral artery (FA) access have mixed results. Methods: Using a large state-wide database, 14,077 patients (8,539 with RA and 5,538 patents with FA access) were retrospectively compared to assess the occurrence of AKI following PCI. To reduce selection bias and balance clinical data across the two groups, a novel machine learning method called a Generalized Boosted Model was conducted on the arterial access site generating a weighted propensity score for each variable. A logistic regression analysis was then performed on the occurrence of AKI following PCI using the weighted propensity scores from the Generalized Boosted Model. Results: As shown in other studies, multiple variables were associated with an increase in AKI after PCI. Only RA access (OR 0.82; 95% CI 0.74-0.91) and male gender (OR 0.80; 95% CI 0.72-0.89) were associated with a lower occurrence of AKI. Based on the calculated Mehran scores, patients were stratified into groups with an increasing risk of AKI. RA access was consistently found to have a lower risk of AKI compared with FA access across these groups of increasing risk. Conclusions: Compared with FA access, RA access is associated with an 18% lower rate of AKI following PCI. This effect was observed among different levels of risk for developing AKI. Although developed from a retrospective analysis, this study supports the use of RA access when technically possible in a diverse group of patients.

Cardiac Manifestations of Adrenal Insufficiency.

It is estimated that the prevalence of primary adrenal insufficiency (Addison disease) is 1 in 10,000 people. There are multiple case reports and several studies that suggest a correlation between Addison disease and abnormalities of cardiac function. The pathophysiology of cardiac abnormalities in this condition is incompletely understood. This review explores what is currently known about the cardiac manifestations of Addison disease.

C-Terminally fused affinity Strep-tag II is removed by proteolysis from recombinant human erythropoietin expressed in transgenic tobacco plants.

KEY MESSAGE: C -terminally fused Strep -tag II is removed from rhuEPO expressed in tobacco plants. The finding suggests that direct fusion of purification tags at the C -terminus of rhuEPO should be avoided. Asialo-erythropoietin (asialo-EPO), a desialylated form of EPO, is a potent tissue-protective agent. Recently, we and others have exploited a low-cost plant-based expression system to produce recombinant human asialo-EPO (asialo-rhuEPO(P)). To facilitate purification from plant extracts, Strep-tag II was engineered at the C-terminus of EPO. Although asialo-rhuEPO(P) was efficiently expressed in transgenic tobacco plants, affinity purification based on Strep -tag II did not result in the recovery of the protein. In this study, we investigated the stability of Strep-tag II tagged asialo-rhuEPO(P) expressed in tobacco plants to understand whether this fused tag is cleaved or inaccessible. Sequencing RT-PCR products confirmed that fused DNA sequences encoding Strep-tag II were properly transcribed, and three-dimensional protein structure model revealed that the tag must be fully accessible. However, Western blot analysis of leaf extracts and purified asialo-rhuEPO(P) revealed that the Strep-tag II was absent on the protein. Additionally, no peptide fragment containing Strep-tag II was identified in the LC-MS/MS analysis of purified protein further supporting that the affinity tag was absent on asialo-rhuEPO(P). However, Strep-tag II was detected on asialo-rhuEPO(P) that was retained in the endoplasmic reticulum, suggesting that the Strep-tag II is removed during protein secretion or extraction. These findings together with recent reports that C-terminally fused Strep-tag II or IgG Fc domain are also removed from EPO in tobacco plants, suggest that its C-terminus may be highly susceptible to proteolysis in tobacco plants. Therefore, direct fusion of purification tags at the C-terminus of EPO should be avoided while expressing it in tobacco plants.

Cardiac manifestations of cutaneous disorders.

A number of cutaneous disorders encountered by the dermatologist have overlapping cardiac pathology. In recent years, many genetic linkages common to pathological processes in the cutaneous and cardiovascular systems have been identified. This review will describe primary cutaneous disorders with potential cardiac manifestations, including congenital syndromes, inherited cutaneous disorders associated with later cardiovascular disease, and syndromes associated with early cardiovascular pathology. The dermatologist may be the first to diagnose cutaneous findings associated with underlying cardiovascular disease; therefore, it is of prime importance for the dermatologist to be aware of these associations and to direct the appropriate workup.

Asialo-rhuEPO as a Potential Neuroprotectant for Ischemic Stroke Treatment.

Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently translated in clinical trials. The clinical failure of rhuEPOM was thought to be mainly due to its erythropoietic activity-associated side effects. To exploit its tissue-protective property, various EPO derivatives with tissue-protective function only have been developed. Among them, asialo-rhuEPO, lacking terminal sialic acid residues, was shown to be neuroprotective but non-erythropoietic. Asialo-rhuEPO can be prepared by enzymatic removal of sialic acid residues from rhuEPOM (asialo-rhuEPOE) or by expressing human EPO gene in glycoengineered transgenic plants (asialo-rhuEPOP). Both types of asialo-rhuEPO, like rhuEPOM, displayed excellent neuroprotective effects by regulating multiple cellular pathways in cerebral I/R animal models. In this review, we describe the structure and properties of EPO and asialo-rhuEPO, summarize the progress on neuroprotective studies of asialo-rhuEPO and rhuEPOM, discuss potential reasons for the clinical failure of rhuEPOM with acute ischemic stroke patients, and advocate future studies needed to develop asialo-rhuEPO as a multimodal neuroprotectant for ischemic stroke treatment.

N-Glycosylation engineering of tobacco plants to produce asialoerythropoietin.

UNLABELLED: Erythropoietin (EPO) is a glycoprotein hormone that displays both hematopoietic and tissue-protective functions by binding to two distinct receptors. Recombinant human EPO (rhuEPO) is widely used for the treatment of anemia, but its use for tissue protection is limited because of potentially harmful increases in red blood cell mass when higher doses of rhuEPO are used. Recent studies have shown that asialoerythropoietin (asialo-rhuEPO), a desialylated form of rhuEPO, lacks hematopoietic activity, but retains cytoprotective activity. Currently, a small amount of asialo-rhuEPO is produced by enzymatic desialylation of rhuEPO. The prohibitive cost of rhuEPO, however, is a major limitation of this method. Plants have the ability to synthesize complex N-glycans, but lack enzymatic activities to add sialic acid and ß1,4-galactose to N-glycan chains. Plants could be genetically engineered to produce asialo-rhuEPO by introducing human ß1,4-galactosyltransferase. The penultimate ß1,4-linked galactose residues are important for in vivo biological activity. In this proof of concept study, we show that tobacco plants co-expressing human ß1,4-galactosyltransferase and EPO genes accumulated asialo-rhuEPO. Purified asialo-rhuEPO binds to an Erythrina cristagalli lectin column, indicating that its N-glycan chains bear terminal ß1,4-galactose residues and that the co-expressed GalT is functionally active. Asialo-rhuEPO interacted with the EPO receptor (EPOR) with similar affinity as rhuEPO, implying that it was properly folded. The strategy described here provides a straightforward way to produce asialo-rhuEPO for research and therapeutic purposes. KEY MESSAGE: N-glycosylation pathway in tobacco plants could be genetically engineered to produce a tissue-protective cytokine, asialoerythropoietin (a desialylated form of human hormone erythropoietin).

A Novel Plant-Produced Asialo-rhuEPO Protects Brain from Ischemic Damage Without Erythropoietic Action.

Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been shown to be a multimodal neuroprotectant targeting an array of key pathological mechanisms in experimental stroke models. However, the rhuEPOM clinical trials were terminated due to increased risk of thrombosis, largely ascribed to its erythropoietic function. We recently took advantage of a plant-based expression system lacking sialylation capacity to produce asialo-rhuEPOP, a rhuEPO derivative without sialic acid residues. In the present study, we proved that asialo-rhuEPOP is non-erythropoietic by repeated intravenous injection (44 µg/kg bw) in mice showing no increase in hemoglobin levels and red blood cell counts, and confirmed that it is non-immunogenic by measuring humoral response after immunizing the mice. We demonstrate that it is neuroprotective in a cerebral ischemia and reperfusion (I/R) mouse model, exhibiting ~ 50% reduction in cerebral infarct volume and edema, and significant improvement in neurological deficits and histopathological outcome. Our studies further revealed that asialo-rhuEPOP, like rhuEPOM, displays pleiotropic neuroprotective effects, including restoring I/R-interrupted mitochondrial fission and fusion proteins, preventing I/R injury-induced increase in mitophagy and autophagy markers, and inhibiting apoptosis to benefit nerve cell survival. Most importantly, asialo-rhuEPOP lacking erythropoietic activity and immunogenicity holds great translational potential as a multimodal neuroprotectant for stroke treatment.

Quantitative Proteomics Reveals the Beneficial Effects of Low Glucose on Neuronal Cell Survival in an in vitro Ischemic Penumbral Model.

Understanding proteomic changes in the ischemic penumbra are crucial to rescue those salvageable cells and reduce the damage of an ischemic stroke. Since the penumbra region is dynamic with heterogeneous cells/tissues, tissue sampling from animal models of stroke for the molecular study is a challenge. In this study, cultured hippocampal HT22 cells under hypoxia treatment for 17.5 h with 0.69 mM low glucose (H+LG) could mimic ischemic penumbral cells since they had much higher cell viability and viable cell number compared to hypoxia without glucose (H-G) treatment. To validate established cell-based ischemic penumbral model and understand the beneficial effects of low glucose (LG), quantitative proteomics analysis was performed on H+LG, H-G, and normoxia with normal 22 mM glucose (N+G) treated cells. We identified 427 differentially abundant proteins (DAPs) between H-G and N+G and further identified 105 DAPs between H+LG and H-G. Analysis of 105 DAPs revealed that LG promotes cell survival by activating HIF1α to enhance glycolysis; preventing the dysregulations of extracellular matrix remodeling, cell cycle and division, and antioxidant and detoxification; as well as attenuating inflammatory reaction response, protein synthesis and neurotransmission activity. Our results demonstrated that this established cell-based system could mimic penumbral conditions and can be used for molecular studies.

Chronic kidney disease and dipstick proteinuria are risk factors for stent thrombosis in patients with myocardial infarction.

BACKGROUND: Kidney failure (stage 5 chronic kidney disease [CKD]) is an independent risk factor for stent thrombosis (ST). Moderate (stage 3-4) CKD and proteinuria are both associated with adverse cardiovascular events, including worse outcomes after myocardial infarction (MI). Whether moderate CKD and proteinuria increase the risk of ST after MI is not known. This study evaluated the risk of ST associated with moderate CKD and dipstick proteinuria. METHODS: We retrospectively analyzed clinical and laboratory data from 956 non-stage 5 CKD patients who were admitted with MI and received intracoronary stenting. Clinical follow-up was collected at 1 year for definite or probable ST, as well as for all-cause mortality, nonfatal MI or death, and target vessel revascularization or coronary artery bypass graft surgery. RESULTS: After adjustment for multiple clinical and biochemical covariates, patients with both estimated glomerular filtration rate (GFR) of 15 to 59 mL min(-1) 1.73 m(-2) and > or =30 mg/dL dipstick proteinuria had increased cumulative incidence of ST (hazard rate [HR] 3.69, 95% CI 1.54-8.89), all-cause mortality (HR 2.68, 95% CI 1.34-5.37), and nonfatal MI or death (HR 3.20, 95% CI 1.77-5.81) at 1 year. In addition, estimated GFR of 15 to 59 mL min(-1) 1.73 m(-2) was a significant independent predictor of ST (HR 2.61, 95% CI 1.33-5.10). Dipstick proteinuria > or =30 mg/dL was associated with a trend toward increased risk for all outcomes. CONCLUSIONS: In an acute MI population, moderate CKD was identified as a novel prognostic marker for ST. In addition, patients with both decreased GFR and proteinuria had higher incidences of all-cause mortality and nonfatal MI or death than patients with either condition alone.

Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries.

Human tissue transglutaminase (TGM2) is a calcium-dependent crosslinking enzyme involved in the posttranslational modification of intra- and extracellular proteins and implicated in several neurodegenerative diseases. To find specific inhibitors to TGM2, two structurally diverse chemical libraries (LOPAC and Prestwick) were screened. We found that ZM39923, a Janus kinase inhibitor, and its metabolite ZM449829 were the most potent inhibitors with IC(50) of 10 and 5 nM, respectively. In addition, two other inhibitors, including tyrphostin 47 and vitamin K(3), were found to have an IC(50) in the micromolar range. These agents used in part a thiol-dependent mechanism to inhibit TGM2, consistent with the activation of TGM2 by reduction of an intramolecular disulfide bond. These inhibitors were tested in a polyglutamine-expressing Drosophila model of neurodegeneration and found to improve survival. The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases.

Myocardial necrosis in patients with thrombotic thrombocytopenic purpura: pathophysiology and rationale for specific therapy.

Myocardial necrosis is now recognized as a common feature of thrombotic thrombocytopenic purpura (TTP), usually due to platelet plugging in the microvasculature. Despite reports that TTP patients with myocardial damage have higher morbidity and mortality, there are no established guidelines for managing these high-risk patients. The universal occurrence of thrombocytopenia and variable findings including renal dysfunction present unique challenges in this setting. Established therapies including plasma exchange and immunosuppression are the mainstay of therapy for all TTP patients. For the subset of patients with myocardial damage, therapy with more potent antiplatelet drugs, agents that enhance NO availability and alleviate vasospasm and drugs that suppress von Willebrand factor levels may have additional benefit. However, clinical trials are needed to optimize therapy for this subset of TTP patients.

A plasma cell-based pericardial effusion leading to tamponade in a patient with multiple myeloma - a case report and review of the literature.

A rare case of extramedullary multiple myeloma causing cardiac tamponade secondary to a plasma cell-based pericardial effusion is described. A systematic search using PubMed (National Library of Medicine) was used to identify a further 27 cases dating back to 1970. Case characteristics, treatment strategies, and survival time following tamponade are discussed. Linear regression demonstrated a weak but statistically significant correlation between survival time following tamponade and treatment with systemic chemotherapy and steroids (ß=16.8 weeks, P=.009). However, this manifestation of extramedullary multiple myeloma still conveys a dismal prognosis with a median survival following tamponade of only 6 weeks based on our review.

Recombinant asialoerythropoetin protects HL-1 cardiomyocytes from injury via suppression of Mst1 activation.

BACKGROUND: Recombinant human erythropoietin (rhuEPO) and asialoerythropoietin (asialo-rhuEPO) are cardioprotective. However, the protective effects of rhuEPO could not be translated into clinical practice because of its hematopoiesis-associated side effects while non-erythropoietic asialo-rhuEPO is unavailable in large quantities for clinical studies. This study was designed to investigate the cardiomyocyte protective potential of plant-produced asialo-rhuEPO (asialo-rhuEPOP) against staurosporine (STS)-induced injury in HL-1 murine cardiomyocytes and identify cellular pathway(s) responsible for its cardioprotection. METHODS: HL-1 cardiomyocytes were simultaneously treated with STS and asialo-rhuEPOP. Cellular injury, apoptosis, and cell viabilities were measured by LDH assay, Hoechst staining and trypan blue exclusion method, respectively while western blotting was used to study its effects on apoptosis and autophagy hallmarks. RESULTS: Our results showed that 20 IU/ml asialo-rhuEPOP provided 39% protection to cardiomyocytes compared to STS-treated cells, which is 2-fold better than that of mammalian cell-produce rhuEPO (rhuEPOM). Asialo-rhuEPOP was found to suppress activation of proapoptotic kinase Mst1 (mammalian Sterile-20-like kinase 1) and FOXO3, leading to inhibition of apoptotic pathway and restoration of autophagy as indicated by the reduction of fragmented/condensed nuclei, altered ratios of Bax/Bcl2, p-Bad/Bad, cytosol/mitochondrial cyt c and caspase-3 activation, and the restored levels of autophagy markers Beclin1, p62 and LC3B-II. Additionally, Akt was found to be activated and FOXO3 was phosphorylated on Ser253, suggesting inhibition of FOXO3 transcriptional function. CONCLUSIONS: Asialo-rhuEPOP-mediated cardioprotection occurs through activation of PI3K/Akt pathway leading to suppression of Mst1 activation and promoting cardiomyocyte survival. GENERAL SIGNIFICANCE: Asialo-rhuEPOP could be used to modulate Mst1 activity elevated under numerous pathological states.

Routine hematologic clinical tests as prognostic markers in patients with acute coronary syndromes.

Prognostic markers are needed to identify patients with acute coronary syndrome (ACS) who are at high risk for adverse events. Although the search for new biomarkers is quite active, prognostic information is available from routine hematologic tests, such as the complete blood count. For example, elevated white blood cell counts during ACS are associated with increased risk of mortality, heart failure, shock, and left ventricular dysfunction. Anemia is associated with increased risk of mortality, whereas elevated platelet counts predict poorer clinical and angiographic outcomes. In this review, we summarize the literature regarding the use of clinical hematology tests including white blood cell count, hemoglobin and hematocrit values, and platelet count as prognostic markers in patients with ACS, and we describe potential mechanisms to explain these associations.

Derived fibrinogen compared with C-reactive protein and brain natriuretic peptide for predicting events after myocardial infarction and coronary stenting.

BACKGROUND: After myocardial infarction (MI), biomarkers can be helpful to identify patients who might benefit from more intensive therapies. The prothrombin time-derived fibrinogen (PTDF) assay is widely available and relatively inexpensive. We determined whether PTDF predicts events in patients with MI and compared this assay with brain natriuretic peptide (BNP) and C-reactive protein (CRP). METHODS: We retrospectively analyzed data from 915 patients admitted with MI. Follow-up was collected at 1 year for major adverse cardiac events (MACE) defined as death from any cause, nonfatal MI or death, target vessel revascularization, or coronary artery bypass grafting. RESULTS: Patients in the fourth quartile of PTDF were older and had more risk factors but fewer ST-elevation MI and lower peak troponin values. The fourth quartiles of PTDF, CRP, and BNP were associated with increased MACE compared with the first quartiles with hazard ratios of 2.08 (1.30-3.33), 1.94 (1.22-3.07), and 2.56 (1.57-4.18), respectively, findings that remained significant after adjustment. When outcomes by strata of PTDF were examined, CRP failed to add additional prognostic value. Higher BNP levels predicted MACE in the upper but not lower stratum of PTDF. CONCLUSION: In patients with MI, PTDF is a predictor of MACE at 1 year, with equivalent value compared to BNP and CRP. With low PTDF levels, neither BNP nor CRP adds prognostic value. At elevated PTDF values, higher BNP, but not CRP, identifies a higher-risk population. Therefore, PTDF can be substituted for CRP, with BNP being useful in the presence of elevated PTDF.

Myocardial infarction in thrombotic thrombocytopenic purpura: a single-center experience and literature review.

BACKGROUND: Several case reports and series have described myocardial infarctions (MIs) in patients hospitalized for thrombotic thrombocytopenic purpura (TTP). The exact magnitude and outcome of this complication are unknown. METHODS: Electronic medical records for patients admitted to Wake Forest University Baptist Medical Center were examined from 1996 to 2005. Those patients having a diagnosis of TTP during the hospitalization period were included in the analysis. Only patients' initial episodes of TTP were analyzed. Baseline cardiac and TTP risk factors were documented. Outcomes analyzed included MIs, arrhythmias, development of congestive heart failure and death. RESULTS: Eighty-five patients diagnosed with TTP were identified with 13 (15.3%) having MIs, as defined by an elevation of cardiac enzymes. Median troponin I value was 5.9 ng/mL (range 3.7-8.8 ng/mL). Twelve patients had non-ST segment elevation MIs and one had ST segment elevation. Two of 13 patients who had echocardiographic analysis had documented wall motion abnormalities. There was no difference between non-MI and MI patients in cardiac risk factors, prior cardiac events, history of thromboembolic disease or heart failure. There was no in-hospital mortality difference. CONCLUSION: MI is an important complication of TTP, identified in 15.3% of patients in our study. Routine cardiovascular evaluation with cardiac enzymes, electrocardiography, and telemetry is warranted in acute TTP patients. Appropriate intervention is yet to be determined.

ABO blood types: influence on infarct size, procedural characteristics and prognosis.

INTRODUCTION: Patients with non-O blood groups have higher plasma von Willebrand factor (vWF) levels than those with type O. vWF mediates platelet adhesion, aggregation and thrombosis. These considerations likely explain the prior observations that non-O patients have higher rates of arterial and venous thromboembolic events. However, the effect of blood group status on size of MI, procedural findings and outcomes after PCI for MI have not been reported. METHODS: We analyzed 1198 patients who underwent percutaneous coronary intervention for acute myocardial infarction between 10/03 and 8/06, and who had ABO blood group status and clinical follow-up. RESULTS AND CONCLUSIONS: Patients with O blood type were slightly older (62 +/- 13 vs. 60 +/- 13 years; p = 0.017) had a higher prevalence of hypercholesterolemia (67% vs. 58%; p = 0.002), and had a higher burden of atherosclerosis with more vascular disease (17% vs. 13%; p = 0.017) and higher prevalence of previous PCI (22% vs. 17%; p = 0.025). Non-O blood group patients had larger infarcts as measured by median peak troponin (33 vs. 24; p = 0.037), total CK (721 vs. 532; p = 0.012) and CK-MB (101 vs. 68; p = 0.010). At PCI, non-O patients had increased visible thrombus and reduced TIMI flow pre-procedure. However, there were no differences in procedural success, in-hospital blood transfusion or occurrence of MACE at 1 year follow-up. Our data demonstrate that non-O compared to O blood groups patients have higher thrombus burden despite less extensive atherosclerosis. Nevertheless, outcomes at 1 year were similar.

Angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy.

BACKGROUND: Activation of the renin-angiotensin system (RAS) may contribute to the development of alcoholic cardiomyopathy. We evaluated the effect of angiotensin II (Ang II) type 1 receptor (AT1) blockade on the development of alcoholic cardiomyopathy. METHODS AND RESULTS: We serially evaluated left ventricular (LV) and cardiomyocyte function and the RAS over 6 months in 3 groups of instrumented dogs. Eight animals received alcohol (once per day orally, providing 33% of total daily caloric intake); 6 received alcohol and irbesartan (5 mg.kg(-1).d(-1) PO); and 8 were controls. Compared with controls, alcohol ingestion caused sustained RAS activation with progressive increases in plasma levels of Ang II, renin activity, LV angiotensin-converting enzyme activity, and LV myocyte Ang II AT(1) receptor expression. The RAS activation was followed by a progressive fall in LV contractility (E(ES), alcohol-fed dogs 3.9+/-0.8 versus control dogs 8.1+/-1.0 mm Hg/mL); reductions in the peak velocity of myocyte shortening (78.9+/-5.1 versus 153.9+/-6.2 microm/s) and relengthening; and decreased peak systolic Ca2+ transient ([Ca2+]iT) and L-type Ca2+ current (I(Ca,L); P<0.05). Irbesartan prevented the alcohol-induced decreases in LV and myocyte contraction, relaxation, peak [Ca2+]iT, and I(Ca,L). With alcohol plus irbesartan, plasma Ang II, cardiac angiotensin-converting enzyme activity, and AT1 remained close to control values. CONCLUSIONS: Chronic alcohol consumption produces RAS activation followed by progressive cardiac dysfunction. The cardiac dysfunction is prevented by AT1 receptor blockade.

Roles of transglutaminases in cardiac and vascular diseases.

All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

Beyond the platelet count: heparin antibodies as independent risk predictors.

A major potential side effect of heparin is immunogenicity, eliciting antibody development to a protein complex comprised of platelet factor 4 and heparin. Nevertheless, the clinical implications of heparin antibody positive patients remain broad, ranging from no apparent clinical consequences to life-threatening arterial and venous thromboemboli. The "Iceberg Model" has been proposed to depict this spectrum, with a relatively large population of antibody-positive patients forming the base of the iceberg, a smaller population of thrombocytopenic patients in the middle and a limited number of patients with thrombocytopenia and thrombosis comprising the apex. An underlying assumption of this model is that thrombosis occurs only in settings of relative or absolute thrombocytopenia. However, several recent studies suggest that antibody formation to platelet factor 4/heparin complexes, even in the absence of thrombocytopenia, may be associated with thrombotic events. In this review, we summarize these data, consider potential mechanisms for thrombosis, and suggest recommendations for testing and management of antibody-positive patients.