Direct thrombin inhibitors in cardiac disease

Most acute coronary syndromes (ACS) are triggered by platelet-rich thrombus superimposed on disrupted atherosclerotic plaque. Thrombin and platelets both play a role in this process. Whereas unfractionated heparin and aspirin have served as cornerstones in the treatment of ACS, several limitations of heparin provide the impetus to seek out better anticoagulants. Direct thrombin inhibitors such as bivalirudin, hirudin, and argatroban offer several pharmacologic advantages over heparin. Additionally, bivalirudin also appears to provide clinical advantages over unfractionated heparin therapy in ACS patients and those undergoing percutaneous coronary intervention.     

Establishing aversive, but not safe, taste memories requires lateralized pontine-cortical connections

Aversive and safe taste memory processing is dramatically disrupted by bilateral lesions of the pontine parabrachial nucleus (PBN). To determine how such lesions affect patterns of neuronal activation in forebrain, lesions were combined with assessment of cFos-like immunoreactivity (FLI) in insular cortex (IC) and amygdala after conditioned taste aversion (CTA) training. Increases in FLI in amygdala and IC, which are normally seen following novel (versus familiar) CS-US pairing, were eliminated after PBN lesions. This suggests that PBN lesions prevent transmission of critical CS and US information to forebrain regions for the processing of both aversive and safe taste memories. Unilateral asymmetrical lesions of PBN and IC blocked CTA acquisition as well as normal patterns of FLI in amygdala after novel CS-US pairing, an effect not seen when unilateral lesions were confined to a single hemisphere. The crossed-disconnection experiments provide compelling evidence that functional interactions between PBN and IC are required for CTA acquisition, but not for safe taste memory formation and retrieval. The dissociation between effects of the different types of lesions on safe and aversive taste memories supports emerging evidence that the neural underpinnings of the two types of taste learning differ.     

New Anticoagulant Drugs

Arterial and venous thrombosis are major causes of morbidity and mortality. Arterial thrombosis is the most common cause of myocardial infarction, stroke, and limb gangrene. Venous thrombosis leads to potentially fatal pulmonary embolism and to post-phlebitic syndrome. Because arterial thrombi consist of platelet aggregates held together by small amounts of fibrin, strategies to inhibit arterial thrombogenesis focus mainly on blocking platelet function, but often include anticoagulants to prevent fibrin deposition. Anticoagulants are used for the prevention and treatment of venous thrombosis because venous thrombi consist mainly of fibrin and red blood cells. This paper (1) reviews arterial and venous thrombogenesis, (2) outlines new anticoagulant strategies, and (3) provides clinical perspectives on these new strategies.     

Syndecan-1 expression is diminished in acantholytic cutaneous squamous cell carcinoma

Syndecan-1 is a cell surface proteoglycan predominantly expressed on the surface of adult epithelial cells, and is normally present in all epidermal layers except for the most superficial terminally differentiated cells. Syndecan-1 mediates cell-cell and cell-extracellular matrix adhesion, thereby influencing cell morphology and growth characteristics. In addition, in vitro studies have shown that expression of syndecan-1 on tumor cells inhibits their invasion into the extracellular matrix. A total of 23 cutaneous biopsies of squamous cell carcinoma, including acantholytic squamous cell carcinoma, invasive squamous cell carcinoma which was not acantholytic, and squamous cell carcinoma in situ were examined for syndecan-1 immunoreactivity. The level of syndecan-1 expression was related to the degree of squamous cell dyshesion, with expression being greatest in the in situ lesions and least in the acantholytic lesions. The loss of syndecan-1 expression with increasing dyshesion of squamous cell carcinoma may be a mechanism for loosening of intercellular and cell-extracellular matrix attachments, thereby promoting the invasion of neoplastic cells into the dermis.     

The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

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Fibrinolysis: strategies to enhance the treatment of acute ischemic stroke

Summary

Stroke is a major cause of disability worldwide, and is the second leading cause of death after ischemic heart disease. Until recently, tissue‐type plasminogen activator (t‐PA) was the only treatment for acute ischemic stroke. If administered within 4.5 h of symptom onset, t‐PA improves the outcome in stroke patients. Mechanical thrombectomy is now the preferred treatment for patients with acute ischemic stroke resulting from a large‐artery occlusion in the anterior circulation. However, the widespread use of mechanical thrombectomy is limited by two factors. First, only ? 10% of patients with acute ischemic stroke have a proximal large‐artery occlusion in the anterior circulation and present early enough to undergo mechanical thrombectomy within 6 h; an additional 9–10% of patients presenting within the 6–24‐h time window may also qualify for the procedure. Second, not all stroke centers have the resources or expertise to perform mechanical thrombectomy. Nonetheless, patients who present to hospitals where thrombectomy is not an option can receive intravenous t‐PA, and those with qualifying anterior circulation strokes can then be transferred to tertiary stroke centers where thrombectomy is available. Therefore, despite the advances afforded by mechanical thrombectomy, there remains a need for treatments that improve the efficacy and safety of thrombolytic therapy. In this review, we discuss: (i) current treatment options for acute ischemic stroke; (ii) the mechanism of action of fibrinolytic agents; and (iii) potential strategies to manipulate the fibrinolytic system to promote endogenous fibrinolysis or to enhance the efficacy of fibrinolytic therapy.

     

Human tissue-type plasminogen activator releases fibrinopeptides A and B from fibrinogen.

In five patients with venous thromboembolic disease treated with recombinant tissue-type plasminogen activator (rt-PA), there was a marked increase in the mean concentrations of fibrinopeptide A (from 0.6 to 5.9 nM; P less than 0.0001) and desarginine fibrinopeptide B (from 5.6 nM to 24.1 nM; P less than 0.01) 30 min after a bolus of rt-PA (0.6 mg/kg). Thrombin was unlikely to be responsible because the levels of desarginine fibrinopeptide B exceeded those of fibrinopeptide A and the changes occurred despite concomitant heparin therapy. The purpose of this study therefore, was to determine whether rt-PA directly releases the fibrinopeptides from fibrinogen. Incubation of rt-PA with heparinized plasma or purified fibrinogen resulted in time and dose-dependent release of both fibrinopeptide A and B. Contaminating thrombin was not responsible for this activity by the following criteria: the rate of rt-PA mediated fibrinopeptide B release was considerably faster than that of fibrinopeptide A, and fibrinopeptide release was unaffected by heparin, hirudin, or a monospecific antithrombin IgG. Aprotinin also had no effect on fibrinopeptide release, indicating that this activity was not plasmin mediated. Fibrinopeptide release was shown to be due to rt-PA because this activity was completely blocked by a monoclonal antibody against the enzyme. Further, the specificity of rt-PA for the thrombin cleavage sites on fibrinogen was confirmed by the demonstration that rt-PA released fibrinopeptide A or fibrinopeptide B from fibrinopeptide A or B-containing substrates, respectively. These studies thus demonstrate that (a) rt-PA releases fibrinopeptides A and B from fibrinogen thereby indicating that this enzyme is not specific for plasminogen, and (b) plasma fibrinopeptide A and desarginine fibrinopeptide B levels are not specific markers of thrombin action on fibrinogen in patients receiving rt-PA.