Vascular damages

The concentration of t-PA in human blood is 2—5 ng/mL, ie, 2—5 ppb. Plasminogen activation is accelerated in the presence of a clot, but the rate is slow. The dissolution of a clot requites a week or more during normal repair of vascular damage (17). Prevention of irreversible tissue damage during a heart attack requires that a clot, formed by mpture of an atherosclerotic plaque, be dissolved in a matter of hours. This rapid thrombolysis (dissolution of the clot) must be achieved without significant tibrinogenolysis elsewhere in the patient. 

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

There is a long-standing hypothesis that the microvasculature plays a pathological role in forms of chronic inflammatory polyarthritis, particularly RA (Rothschild and Masi, 1982). One of the proposed mechanisms of vascular damage in connective tissue disease is the direct action of a cytotoxic serum factor inducing endothelial cell damage. Blake et al. (1985) have su ested that the vascular abnormalities associated with RA may be linked to oxidized lipoproteins because they are cytotoxic to endothelial cells. 

Several distinct biochemical mechanisms have been proposed to account for free-radical-induced vascular damage in diabetes. 

Routine antioxidant vitamin supplementation, e.g. with vitamins C and/or E, of the diabetic diet should be considered. Vitamin C depletion is present in all diabetics irrespective of the presence of vascular disease. A recent study demonstrated no significant difference between the dietary intake of vitamin C (the main determinant of plasma ascorbate) in patients with diabetes and age-matched controls, confirming the view that ascorbate depletion is secondary to the diabetic process and su esting that diabetic patients require additional intakes of the vitamin to maintain optimal levels (Sinclair et /., 1994). Antioxidant supplementation may have additive beneficial effects on a wide variety of processes involved in diabetic vascular damage including blood pressure, immune function, inflammatory reactions. 

Release of markers bound to the endothelial cell such as thrombomodulin is indicative of vascular damage. Increased levels of soluble thrombomodulin in plasma are diagnostic (93). Other endothelium-derived markers such as 6-keto-prostaglandin F a, which is a metabolite of prostacyclin, are useful in the assessment of endothelial function, with lower levels indicative of inability to synthesize this marker due to defective or damaged endothelium through plaque formation (93). 

Klug PP, Kaye N, Jensen WN. Endothelial cell and vascular damage in the sickle cell disorders. Blood Cells 1982 8 175-184. 

Blood plays various vital roles within the body and it is not surprising that a number of processes have evolved capable of effectively maintaining haemostasis (the rapid arrest of blood loss upon vascular damage, in order to maintain a relatively constant blood volume). In humans, three main mechanisms underline the haemostatic process ... 

Figure 12.5 Proteolytic cleavage of prothrombin by factor Xa, yielding active thrombin. Although prothrombin is a single-chain glycoprotein, thrombin consists of two polypeptides linked by what was originally the prothrombin intrachain disulfide bond. The smaller thrombin polypeptide fragment consists of 49 amino acid residues, and the large polypeptide chain contains 259 amino acids. The N-terminal fragment released from prothrombin contains 274 amino acid residues. Activation of prothrombin by Xa does not occur in free solution, but at the site of vascular damage...

P2Y receptors that are found on endothelial cells elicit a Ca2+-dependent release of endothelium-dependent relaxing factor (EDRF) and vasodilation. A secondary activation of a Ca2+-sensitive phospholipase A2 increases the synthesis of endothelial prostacyclin, which limits the extent of intravascular platelet aggregation following vascular damage and platelet stimulation. The P2Y-mediated vasodilation opposes a vasoconstriction evoked by P2X receptors located on vascular smooth muscle cells. The latter elicit an endothelial-independent excitation (i.e. constriction). P2Y receptors are also found on adrenal chromaffin cells and platelets, where they modulate catecholamine release and aggregation respectively. 

Intrinsic Vascular damage Hypercalcemia Hepatorenal syndrome Vasculitis Polyarteritis nodosa Hemolytic uremic syndrom thrombotic thrombocytopenic purpura Emboli Atherosclerotic Thrombotic... 

Normally, quiescent platelets freely circulate through the vasculature, reflective of the hemocompatible character of the vascular endothelium and the anti-thrombotic nature of healthy human blood vessels. Traumatic vascular damage incites a spatially and temporally coordinated platelet transformation encompassing several major, sequential phenotypic changes platelet adhesion to subendothelial matrix components... 

Apart from inducing vascular damage via infiltration and degranulation of various blood cells, PAF and TNF exert also direct effects in the endothelium. In vitro, both substances cause contraction of endothelial cells, which may partially account for the increased vascular permeability and plasma extravasation observed in many species following PAF or TNF administration [311]. While it has been known for some time that endothelial cells produce PAF when stimulated with various agonists such as thrombin, it has recently been established that TNF and IL-1 also induce cultured endothelial cells to synthesize PAF, the majority of which remains associated with the cells [317]. 

P an, A. Y. S., and Z. Jegier. Trypsin protein esterase in relation to ozone-induced vascular damage. Arch. Environ. Health 24 233-236, 1972. 

Arterial hypertension (high blood pressure) generally does not impair the well-being of the affected individual however, in the long term it leads to vascular damage and secondary complications (A). The aim of antihypertensive therapy is to prevent the latter and, thus, to prolong life expectancy. 

The minimal lethal dose in mice by subcutaneous injection was 180mg/kg animals developed progressive cyanosis and dyspnea before death at autopsy there were degenerative lesions in the liver, kidneys, and other organs, with evidence of vascular damage. ... 

Gi effects Vomiting, diarrhea, abdominal pain, and nausea may occur, especially with maximum doses. These may be particularly troublesome in the presence of peptic ulcer or spastic colon. At toxic doses, colchicine may cause severe diarrhea, generalized vascular damage, and renal damage with hematuria and oliguria. To avoid more serious toxicity, discontinue use when these symptoms appear, regardless of whether joint pain has been relieved. 

Pathophysiologically, although vascular damage and platelet involvement occurs, the major component in the clot is fibrin. 

Systemic arterial hypertension ( high blood pressure ) does not typically make the afflicted individual feel unwell however, after many years, it leads to vascular damage and to the secondary complications thereof hence, the designation of hypertension as the silent killer. The ultimate aim of the pharmacological management of hypertension is to prevent these complications and thus to prolong not only life expectancy but also quality of life. 

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