Gene/Protein Disease Symptom Drug Enzyme Compound
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Laryngeal cancer is the most common neoplasm of the head and neck region. Laryngeal cancer patients experience thromboembolic complications more often than the general population. Our previous studies revealed in loco activation of blood coagulation in laryngeal cancer. The purpose of the present study was to examine the interactions among the laryngeal cancer cells and fibrinolytic system components in loco. Twenty-two cases of squamous carcinoma of the larynx were examined. AMeX method-preserved cancer tissues were examined using immunohistochemical ABC method. Fibrin and D-D fibrin dimers were demonstrated in the matrix, predominantly on the tumor-host front. Plasminogen, tissue-type plasminogen activator (t-PA) and plasmin were detected in cancer cells, but the intensity of their expression revealed a negative correlation with the degree of malignancy. A weak expression of high molecular weight urokinase (HMW-UK) was observed in cancer cells in the centers of the cancer foci, and a product of its degradation--low molecular weight urokinase (LMW-UK) was observed in cancer cells on the invasion front. The presence of plasminogen activator inhibitors (PAI-1, PAI-2, PAI-3) was also documented in the cancer cells. The expression of urokinase receptor (u-PAR) was very weak. Based on the results of the study, we suggest that in laryngeal cancer a suboptimal activation of fibrinolysis occurs that contributes to fibrin deposition in the tumour.
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PMID:[The location of components of fibrinolytic system in laryngeal cancer]. 1459 67

Semen contains enzymes and inhibitors of the haemostatic system as well as the high molecular weight seminal vesicle (HMW-SV) proteins. The former may have roles in seminal clotting and in liquefaction through "fibrinolytic" activity, which may ultimately affect fertility. Although a limited number of studies have addressed the subject, the role of clotting and fibrinolytic factors in semen remains poorly understood. The liquefaction time and the distribution of components vary across split ejaculates. This may have an important bearing on the way clotting/fibrinolytic factors in semen are assessed. Semen contains tissue factor (TF, Thromboplastin, CD142), which originates from the prostate and is associated with prostasomes. The function of TF (and prostasomes) in semen is still a matter for speculation. Recently the presence of minute amounts of factor VII in semen has been demonstrated but its importance is uncertain. Semen also contains a thrombin-like enzyme, prothrombin fragments 1 and 2 (F1+2), D-dimer (DD) and thrombin-antithrombin (TAT) complexes. The presence of several fibrinolytic factors has been demonstrated in semen but few questions about their potential impact on semen quality have been raised. Factors found include tissue plasminogen activator (t-PA), urinary plasminogen activator (u-PA) and plasmin. There are also traces of fibrinogen, plasminogen, plasminogen activator inhibitor-1 (PAI-1), factor VIII coagulant activity (VIII:c) and fibrin monomers. The co-ordinate expression of both TF and PAI-1 by decidual cells of the endometrium is believed to be important in maintaining haemostasis during endovascular trophoblast invasion. Kallikrein-like serine protease inhibitors including prostate specific antigen (PSA) are known to be present in semen at high concentrations. In semen PSA is also found in a complex form with protein C inhibitor (PCI) with mutually inhibitory consequences. A better understanding of the spectrum of coagulating and liquefaction agents in semen to include classical haemostatic processes and the pathogenesis resulting from any imbalances between or within either system may provide the basis for the development of more selective and efficient agents affecting global fertility. Here we review aspects of male reproductive physiology in the light of recent findings concerning conventional clotting/fibrinolytic systems in human semen with a view to stimulating further research.
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PMID:Seminal clotting and fibrinolytic balance: a possible physiological role in the male reproductive system. 1546 6

There is no uniform approach to treating the 1.5 million US citizens who have an acute myocardial infarction (AMI) each year. This contrasts with the trauma system developed to efficiently triage and treat the critically injured accident victim. Only two thirds of patients with ST-segment elevation AMI in the United States are treated with thrombolytic therapy or primary angioplasty (percutaneous coronary intervention [PCI]) which can reduce the 30-day mortality rate from approximately 15% to 6%-10%. The Early Retavase-Thrombolysis in Myocardial Infarction (ER-TIMI) 19 trial demonstrated that AMI patients who received prehospital thrombolytic therapy and were brought to the nearest receiving hospital experienced a 32-minute reduction in the time to treatment and time to ST-elevation resolution compared with those treated at their time of hospital arrival. This expedited therapy was associated with a low in hospital mortality rate (4.7%). The potential benefit of facilitated PCI with partial-dose thrombolysis and abciximab administration was demonstrated by the Strategies for Patency Enhancement in the Emergency Department (SPEED) investigators who found that double bolus recombinant plasminogen activator (reteplase) (5 + 5 megaunits) and abciximab with the addition of early PCI, resulted in a final infarct-related artery TIMI 3 flow rate of 86% compared with 77% with combination therapy alone. The Primary Angioplasty in Acute Myocardial Infarction (PAMI) investigators have shown that patients admitted with infarct-related artery TIMI 3 flow at the time of primary PCI had less than a 1% 6-month mortality. Treating AMI patients with prehospital, partial dose thrombolysis followed by immediate transport to a Level I cardiovascular center (bypassing the closest hospital if necessary) for facilitated infarct-related artery PCI has the potential to reduce the mortality in ST-elevation AMI patients from 6%-10% to less than 4% which could translate into saving approximately 500 lives per day in the United States. It is time to validate this strategy with a randomized clinical trial, the Prehospital Administration of Thrombolytic Therapy With Urgent Culprit Artery Revascularization trial (PATCAR).
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PMID:The level I cardiovascular center: is it time? 1581 38

We are presenting the case of a forty-six-year old patient, with a previously undiagnosed congenital secundum atrial septal defect, admitted to the intensive care ward because of an acute inferior and right ventricular myocardial infarction. He was randomised to Gusto V Trial and intravenous therapy of reteplase and abciximab was administered, which resulted in electrocardiographic reperfusion. After several hours of right ventricular failure his condition improved. No complications were observed throughout the convalescence. During the routine TTE examination a secundum ASD was diagnosed and confirmed afterwards in the TEE examination. Patient was qualified for coronarography which revealed a critical lesion in the right coronary artery; successful PCI was conducted. He is now waiting for surgical correction of a secundum atrial septal defect.
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PMID:[Acute inferior and right ventricular myocardial infarction in a patient with congenital secundum atrial septal defect]. 1678 98

The increasing elderly population will influence the treatment policies adopted in cases of acute myocardial infarction. Considering reperfusion therapy in elderly patients with acute myocardial infarction, we compared three strategies, as follows: primary percutaneous coronary intervention (primary PCI: n = 26), facilitated PCI with half the standard dose of mutant tissue-type plasminogen activator (t-PA) (half + PCI: n = 24), and facilitated PCI with a standard dose of mutant t-PA (standard + PCI: n = 15) between patients 75 and 80 years of age. The rate of acquisition of thrombolysis in myocardial infarction (TIMI-3) flow on initial coronary arteriography was significantly lower in the primary PCI group than in the other two groups (7.7% in the primary PCI group vs 60% in the half + PCI and 66.7% in the standard + PCI group). The incidence of hemorrhagic complications including blood transfusion was not significantly different between primary PCI and facilitated PCI. Considering reperfusion therapy in elderly patients with acute myocardial infarction, we concluded that facilitated PCI may be effective in elderly patients aged 75-80 years.
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PMID:Reperfusion strategy for acute myocardial infarction in elderly patients aged 75 to 80 years. 1686 99

Keratinocytes propagated in low calcium (0.05 mM) serum-free medium grow as monolayers and exhibit morphological and biosynthetic phenotypes similar to the keratinocytes of the basal layer in normal epidermis. When the calcium in the medium is increased to 1.5 mM, the keratinocytes start to stratify and differentiate. Such differentiation is important in the formation of an epidermal barrier. Proteolysis plays a crucial role in the process. The functions of most of the plasminogen activator cascade components in human skin have been studied, but little was known about the expression and role of protein C inhibitor in the differentiation of human epidermal keratinocytes. In the present study, we used immunohistochemistry and immunocytochemistry to examine the immunolocalization of protein C inhibitor in normal human skin and in cultured keratinocytes in serum-free medium with low and high calcium, respectively. The results indicated that protein C inhibitor is mainly localized in superficial and more differentiated keratinocytes in normal human epidermis. Keratinocytes positive for protein C inhibitor were detected in cultures containing both low and high calcium media, and the level of protein C inhibitor was increased in high calcium medium. This increase was accompanied by an altered intracellular distribution, from the perinuclear cytoplasm in undifferentiated keratinocytes to the whole cytoplasm in differentiated keratinocytes. Further study revealed that protein C inhibitor was incorporated into the cornified envelope in normal skin keratinocytes and cultured differentiated keratinocytes. Our results suggest that protein C inhibitor may be involved in the differentiation of keratinocytes.
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PMID:Immunolocalization of protein C inhibitor in differentiation of human epidermal keratinocytes. 1770 50

The Clinical Trials described in this article were presented at the Hotline and Clinical Trial Update Sessions of the European Society of Cardiology Congress held in September 2007 in Vienna, Austria. The sessions chosen for this article represent the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses could alter the final publication of the results of these studies. PROSPECT evaluated echocardiographic criteria for optimal selection of patients with moderate to severe heart failure who may benefit from cardiac resynchronisation therapy, however concluded that no single echocardiographic measure can be recommended. EVEREST found that tolvaptan, a vasopressin V(2) antagonist, resulted in early weight reduction and improvement of dyspnoea in patients with acute heart failure, but lacked long term improvement. In ARISE, the anti-oxidant succinobucal did not affect the primary outcome in high risk cardiovascular patients, but improved the combination of cardiovascular death, myocardial infarction and stroke, and diabetic control in diabetics. ALOFT showed that the addition of the renin inhibitor aliskiren to an ACE inhibitor or ARB and a beta-blocker leads to favourable effects on neurohormonal actions in heart failure. FINESSE markedly improved coronary patency before PCI with half-dose reteplase/abciximab in STEMI patients, however without significantly improving short-term outcome. The Prague-8 Study evaluated whether routine clopidogrel administered >6 h pre-angiography would be a safe way to achieve therapeutic drug levels in case a follow-up intervention would be considered immediately, but appeared not justified because of bleeding complications. CARESS in MI showed that high risk patients with evolving STEMI who undergo thrombolytic therapy should undergo PCI early after the thrombolysis. Finally, the ACUITY trial found that in moderate or high risk Non ST elevation ACS patients triaged to PCI, coronary artery bypass graft (CABG) surgery, or medical management, bivalirudin, with or without associated GPIIb/IIIa inhibitor therapy, resulted in a marked reduction of bleeding at 30 days whilst preserving the ischemic and mortality benefit at 1 year follow up.
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PMID:Clinical trials update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY. 1799 67

This chapter about fibrinolytic, antiplatelet, and antithrombin treatment for acute ST-segment elevation (STE) myocardial infarction (MI) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary percutaneous coronary intervention [PCI] or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A). For patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend administration of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over no fibrinolytic therapy (all Grade 1A). For patients with symptom duration < or = 6 h, we recommend the administration of alteplase or tenecteplase over streptokinase (both Grade 1A). We recommend aspirin over no aspirin therapy followed by indefinite therapy (Grade 1A); we also recommend clopidogrel in addition to aspirin for up to 28 days (Grade 1A). In addition to aspirin and other antiplatelet therapies, we recommend the use of antithrombin therapy (eg, unfractionated heparin (UFH), enoxaparin, or fondaparinux) over no antithrombin therapy (Grade 1A), including for those patients receiving fibrinolysis (and regardless of which lytic agent is administered), primary PCI, or patients not receiving reperfusion therapy.
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PMID:Acute ST-segment elevation myocardial infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). 1857 77

Protein C inhibitor (PCI) is a member of the serine protease inhibitor (serpin) family. PCI was initially found to be an inhibitor of activated protein C, and later shown to be a potent inhibitor of blood coagulation and fibrinolysis such as that mediated by urokinase type-plasminogen activator. Therefore, the protein came to be known as plasminogen activator inhibitor-3. It also inhibits proteases involved in fertilization. PCI is broadly conserved, and is found in human, rhesus monkey, cow, rabbit, rat, mouse and chicken. The human PCI gene is located on chromosome 14q32.1 in a cluster of genes encoding related serpins. Sp1- and AP2-binding sites in the 5'-flanking region act as promoter and enhancer, respectively, for its expression in the liver. PCI mRNA is expressed in many organs in primates, but only in the reproductive organs in rodents. Recent studies using transgenic mice expressing the human gene have suggested that PCI is also involved in regulation of lung remodeling, tissue regeneration, vascular permeability, proteolysis in the kidney and tumor cell invasion. A protease inhibitor-independent activity of PCI, the prevention of anti-angiogenesis and metastasis of tumor cells, has also been observed. Thus, PCI is a unique multi-functional serpin playing diverse roles in the thrombosis and hemostasis in multiple organs and tissues of a variety of species.
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PMID:The multi-functional serpin, protein C inhibitor: beyond thrombosis and hemostasis. 1898 17

A 67-year-old man was admitted to our institution with sudden and persistent chest pain for 3 days. Coronary angiography showed massive thrombotic occlusion of the right coronary artery. The patient received intracoronary thrombolysis with alteplase (recombinant tissue-type plasminogen activator, rt-PA). On repeated angiography, there was marked resolution of intracoronary thrombus. After percutaneous coronary intervention with stent implantation, the final result was complete revascularization of the right coronary artery (TIMI grade 3 distal flow). This case demonstrates that intracoronary rt-PA can result in local thrombus reduction in patients undergoing PCI, especially with a large thrombus burden.
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PMID:Successful revascularization of coronary artery occluded by massive intracoronary thrombi with alteplase and percutaneous coronary intervention. 2046 85


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