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- Volume 10, Issue 2, 2010
Cardiovascular & Haematological Disorders - Drug Targets - Volume 10, Issue 2, 2010
Volume 10, Issue 2, 2010
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Editorial [Hot topic:Thromboembolism in Patients with Malignancy (Guest Editor: Ioannis Starakis)]
More LessIt is well known that malignancy is often associated with a hypercoagulable state. Malignant cells may express procoagulant activity, such as cancer procoagulant and tissue factor, which can unswervingly trigger thrombin production. Additionally, normal host cells (monocytes, platelets, and endothelial cells) may also express or release procoagulants in response to the tumour. Cell adhesion moiety p-selectin, is an important activator of haemostatic mechanisms, which is originated in the alpha granules of platelets and the Weibel-Palade bodies of endothelial cells. Studies in animal models have demonstrated that high plasma levels of p-selectin exhibit prothrombotic activity and also represent an independent predictor of venous thromboembolism in cancer patients. Although mononuclear phagocytes are essentially lacking of any procoagulant activity, they may be triggered by tumour necrosis factor (TNF) and produce tissue factor (TF) and other direct factor X activators, which may modulate immunologic, inflammatory, and haemostatic processes but also promote tumour growth and dissemination. A variety of substances derived from various animal and human tumours, such as tumour cell membrane fragments, may directly aggregate platelets leading to an increased secretory release of growth-promoting activity. Recently, the acknowledgment of this fundamental mutual interaction has led to a better understanding of the linkage between platelet stimulation and tumour dissemination, and has offered new intriguing future options to disrupt this interaction and prevent metastatic spread. Platelet activation may also be achieved through other pathogenetic mechanisms such as high plasma levels of von Willebrand factor (Vwf), ADP generation by malignant cells and tumour-provoked thrombin production. Endothelial cells may exhibit procoagulant activity under the stimulus of TNF. Many researchers have reported that TNF increase IL-1 production by the endothelial cells, represses endothelial fibrinolytic activity, and also suppresses thrombomodulin expression and consequently the activation of protein C in the anticoagulant pathway. There are controversial reports concerning TNF levels in cancer patients and although steadily high levels have been noted, many investigators have only infrequently encountered high TNF plasma levels in malignancies.The hypercoagulable state in malignancy may be merely presented as abnormal coagulation tests or with an assortment of clinical manifestations such as migratory superficial thrombophlebitis (Trousseau's syndrome), idiopathic venous thrombosis and or massive thromboembolism, nonbacterial thrombotic (marantic) endocarditis, disseminated intravascular coagulation, thrombotic microangiopathy and arterial thrombosis. It should be noted that thromboembolic incidents may precede the identification of malignancy by months or even years. Approximately 10% of patients with idiopathic venous thromboembolism are, in fact, harbouring an unidentified malignant disorder. In that case, the malignancy can only be detected by the physician's awareness and high index of suspicion which will eventually lead to an extensive diagnostic evaluation. Nevertheless, there is still an ongoing dispute concerning to the issue whether extensive and costly screening for occult cancer is eventually improving prognosis and patient outcome. Although early observations have noticed that mucin-secreting adenocarcinomas of the gastrointestinal tract were associated with an increased thrombotic potential, many non-mucin producing malignancies are also incriminated and until now the efforts to isolate a unique purified procoagulant molecule from mucin, have failed. A variety of comorbidities may adversely influence thrombotic predisposition in malignancy. Long-term immobilization, surgical intervention, the presence of an indwelling central venous catheter and chemotherapeutic regimens with or without adjuvant hormonal manipulation, are well recognized risk factors which increase thromboembolic tendency in cancer patients. Amongst the chemotherapeutic regimens which have been related to an increased thromboembolic incidence, L-asparaginase and tamoxifen are two of the drugs that are most frequently implicated.
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Nonbacterial Thrombotic Endocarditis (Marantic Endocarditis) in Cancer Patients
Authors: Elias E. Mazokopakis, Periklis K. Syros and Ioannis K. StarakisThe term nonbacterial thrombotic endocarditis (NBTE), or marantic endocarditis, refers to a spectrum of lesions ranging from microscopic aggregates of platelets to large vegetations on previously undamaged heart valves (most often aortic and mitral) in the absence of a bloodstream bacterial infection. NBTE is a rare condition often associated with hypercoagulable states or advanced malignancy such as adenocarcinomas. In this article, the pathogenesis, incidence, clinical manifestations, diagnosis, and management of NBTE in cancer patients are reviewed.
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Thrombotic Microangiopathy and Occult Neoplasia
Authors: Maria Teresa Pirrotta and Alessandro BucalossiThrombotic thrombocytopenic purpura (TTP), which is typically characterized by fever and central nervous system manifestations and hemolytic uremic syndrome (HUS), in which renal failure is a prominent feature are the most common thrombotic microangiopathies (TMAs). TTP is usually associated with a severe deficiency of ADAMTS13 [a metalloproteinase involved in the degradation of von Willebrand factor (vWF) multimers], causing excessive accumulation of ultra-large vWF multimers and platelet aggregation with organ failure. By contrast, patients with HUS or other TMAs usually display a normal or at least detectable ADAMTS13 activity. A TMA may be occasionally developed in association with HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome, infections, cancer and bone marrow transplantation. In cancer patients, TMA may be related to chemotherapeutic regimens or the malignant disease itself. Occasionally, TMA is the first manifestation of an occult cancer, and in large series approximately 3% of patients who were originally diagnosed with TTP, were in fact harboring an occult malignancy. The pathogenesis of cancer-associated TMAs is not completely elucidated, but probably the most important factor is endothelial damage. However, cancer-associated TMAs show some distinct features that should promptly lead to complementary investigations for an underlying malignancy. Weakness, cough and dyspnoea, fever, weight loss, bone and abdominal pain are the most common presenting symptoms. Generally, biochemistry reveals markedly increased LDH levels, increased alkaline phosphatase and the blood smear shows erythromyelemia. Bone marrow biopsy is a valuable tool in order to establishing malignant seeding. Treatment of the underlying neoplasia is the mainstay of therapy and there is no role for plasmapheresis or plasma infusions.
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Drug-Induced Thromboembolic Events in Patients with Malignancy
Authors: Ioannis Starakis, Angelos Koutras and Elias E. MazokopakisPatients with malignancies are often in a hypercoagulable status. The pathogenetic mechanisms of thrombotic events in malignancy are multifaceted and consist of release or expression of procoagulants by cancer cells, but also appearance of procoagulant action by normal host cells. Most importantly, current therapeutic modalities for cancer such as high dose chemotherapy and surgery represent a significant additional risk for serious or even fatal thromboembolic events. There is a wide spectrum of clinical manifestations of these events which encompass Trousseau's syndrome, deep venous thrombosis, marantic endocarditis, disseminated intravascular coagulation, thrombotic microangiopathy and arterial thrombosis. Cancer chemotherapy is most commonly associated with deep vein thrombosis but intracranial sinus vein thromboses and thrombotic microangiopathy may also occur. Our purpose is to review the relevant literature linked to the effect of chemotherapy and other cancer-related interventions on thromboembolic incidents.
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Paradoxical Thrombotic Effects of Aspirin: Experimental Study on 1000 Animals
Authors: Christian Doutremepuich, Omar Aguejouf, Vanessa Desplat and Francisco X. EizayagaAspirin administration decreases the risk of vascular ischemic problems. However, aspirin withdrawal may temporarily increase this risk. Previous studies reported that high dilutions of aspirin might cause a pro-thrombotic effect. This paper studies the effect of the lower end of the aspirin dose-response curve, its possible mechanism and clinical implications. Protocol: Wistar rats were distributed into 100 groups of 10 rats each. Aspirin was injected at 100 mg/kg, 1 mg/kg and at several different aspirin dilutions along with cyclooxygenase (COX) 1 (SC-560), COX 2 (NS-398) or both selective inhibitors simultaneously using a laser-induced thrombosis model. Results: The higher doses of aspirin decreased thrombosis. An opposite trend was observed with the lowest doses. SC-560 produced an anti-thrombotic effect antagonized by the highest aspirin dilutions. NS-398 created a pro-thrombotic effect that was antagonized by aspirin at higher doses. Simultaneous inhibition of COX 1 and 2 produced changes similar to COX 1 inhibition. Conclusion: COX 2 inhibition induced a pro-thrombotic effect that was antagonized by aspirin at 1 mg/kg or 100 mg/kg. The administration of the lowest aspirin doses induced a pro-thrombotic effect stronger than the antithrombotic effect of COX 1 selective inhibition. The mechanism of this last pro-thrombotic effect is induced by residual aspirin and is independent of COX 1 inhibition. This study may explain the cause of the paradoxical thrombo-embolic complications observed after aspirin discontinuation, an effect of residual aspirin rather than a rebound effect, and highlights the importance of low doses of substances as a barely studied source of side-effects.
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A Stress Repair Mechanism That Maintains Vertebrate Structure During Stress
More LessBased on Capillary Gate Theory and Tissue Repair Theory, this paper describes the “Stress Repair Mechanism” (SRM) that maintains and repairs vertebrate tissues. It accounts for most of the mysterious manifestations of allostasis that remain unexplained by Hypothalamic-Pituitary-Axis (HPA) hormones and thereby enables the Universal Theory of Medicine predicted by Hans Selye. SRM activity explains hemodynamic physiology, capillary hemostasis, infarction, Korotkoff sounds, blood pressure, hypertension, diabetes, allostasis, allostatic load, anesthesia, analgesia, atherosclerosis, apoptosis, malignancy, eclampsia, sepsis, Multi-System Organ Failure (MSOF), the surgical stress syndrome, the fight or flight response, and numerous other manifestations of physiology and pathology. SRM function comprises the autonomic nervous system, the vascular endothelium, and the dynamic enzymatic interaction of blood-borne hepatic Factors VII, VIIIC, IX and X that produces thrombin, soluble fibrin and insoluble fibrin, whose combined effects account for all SRM manifestations. The vascular endothelium is a diaphanous neuroendocrine organ that lines all blood vessels and is the sole constituent of capillary walls. It secretes tissue factor into extravascular tissues, and insulates those tissues from the hepatic enzymes, so that tissue disruption exposes tissue factor to the enzymatic interaction and activates tissue repair. The vascular endothelium also releases nitric oxide and von Willebrand Factor into blood in accord with autonomic balance to regulate the enzymatic interaction to govern tissue perfusion and organ function. Therefore, continuously fluctuating combinations of nervous stimuli that affect autonomic balance and forces that disrupt tissues determine SRM activity.
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Evaluation of Vancoplus Versus Ceftriaxone Against Cephalosporin Resistance MRSA Strain in Experimental Meningitis Model
Authors: A. Soni, M. Chaudhary, V. K. Dwivedi, S. Kumar and S. M. ShrivastavaThe aim of this study was to compare the efficacy of ceftriaxone plus vancomycin (Vancoplus) versus ceftriaxone alone against cephalosporin resistant methicillin-resistant Staphylococcus aureus (MRSA) strain by using meningitis mice model. The MRSA strain ATCC 43300 was used to induce meningitis in mice. The mice were fed standard pelleted diet and water ad libitum. The test room was air conditioned with temperature 23 ± 2°C, humidity 65± 5% and with artificial fluorescent light 10-14 hrs. of light and dark, respectively. Twenty four mice were divided into four group containing six rats in each group. The ceftriaxone group received 28.57 mg/Kg body weight/day and the vancoplus group received 42.8 mg/Kg body weight/day and control as well as infected group received normal saline. The bacterial susceptibility test in CSF was performed for cephalosporin resistance MRSA strain by determining the lytic zone for the vancoplus and ceftriaxone antibiotic. The lytic zone was more in vancoplus as compared to ceftriaxone. It was also found that activities of antioxidant enzymes such as catalase were significantly increased (p<0.001) along with decreased (p<0.001) in lipid peroxidation (malonaldialdehyde) level in CSF of vancoplus treated group as compared to infected as well as ceftriaxone resistance group and come back to normal level. It was concluded that vancoplus beneficial for the patients who suffered from cephalosporin resistant MRSA bacterial strain.
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Discussion on Pharmacogenetic Interaction in G6PD Deficiency and Methods to Identify Potential Hemolytic Drugs
Authors: Genesia Manganelli, Annalisa Fico, Giuseppe Martini and Stefania FilosaGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common form of red blood cell enzymopathy. The disorder has reached polymorphic frequencies in different parts of the world due to the relative protection conferred against malaria. G6PD is a housekeeping X-linked gene encoding the first enzyme of the pentose phosphate pathway, an NADPH-producing dehydrogenase. Because erythrocytes do not generate NADPH in any other way than pentose phosphate pathway, they are more susceptible than any other cells to oxidative damages. G6PD deficiency is a prime example of a hemolytic anemia due to an interaction between an intracorpuscular cause and an extracorpuscular cause, because in the majority of cases an exogenous agent triggers hemolysis. Hemolysis, in fact, can be caused by exposure to oxidant agents. Although studies performed on epidemiology, genetics and molecular biology have broaden the information on G6pd deficiency, there are still no reliable and validated methods to test drug hemolytic potential in G6PD deficient patients. The review gives an overview of current knowledge on G6pd deficiency and on the methods that have been developed so far in order to identify drugs causing acute hemolytic anemia in G6pd deficiency. Moreover, we discuss the new potential preclinical strategies to assess, in vitro and in vivo, drug hemolytic risks.
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Diabetes, Hyperglycemia and Accelerated Atherosclerosis: Evidence Supporting a Role for Endoplasmic Reticulum (ER) Stress Signaling
Authors: Cameron S. McAlpine, Anna J. Bowes and Geoff H.WerstuckDiabetes mellitus is associated with both micro- and macrovascular complications that can lead to significantly elevated incidence of retinopathy, nephropathy, neuropathy, myocardial infarction and stroke. The diabetic cardiovascular mortality rate exceeds 70% and individuals with diabetes are 2-3 times more likely to die from myocardial infarction and stroke than those with no history of diabetes even after controlling for other cardiovascular risk factors. Despite the profound clinical importance of vascular disease in patients with diabetes mellitus, our understanding of the molecular and cellular mechanisms by which diabetes promotes these vascular complications is incomplete. Endoplasmic reticulum (ER) stress and the unfolded protein response pathways have been previously associated with the development of several different diseases, including neurodegenerative disorders, cancer, and obesity. In addition, ER stress has been directly implicated in complications that are associated with diabetes, including pancreatic β cell dysfunction and insulin resistance. In this review we examine the potential role of endoplasmic reticulum stress in the initiation and progression of hyperglycemia- associated atherosclerosis.
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Volumes & issues
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)