James L. Gutmann DDS, Cert Endo, PhD, FICD, FACD, FADI

• Professor Emeritus, Baylor College of Dentistry, Texas A & M
• University System, Dallas, Texas, USA

Calciphylaxis describes the tissue ischemia that may result from the calcification of smaller blood vessels and their subsequent thrombosis erectile dysfunction medication australia order sildalist 120mg without a prescription. Chronic hyperphosphatemia contributes to the development of renal osteodystrophy (see Chapter 13 erectile dysfunction and diabetes leaflet cheap sildalist 120mg with mastercard, Renal Diseases) erectile dysfunction 55 years old generic 120mg sildalist overnight delivery. Diagnostic Testing the elevated serum phosphorus can be accompanied by hypocalcemia as a result of intravascular chelation of calcium by phosphorus erectile dysfunction treatment natural food order 120mg sildalist with mastercard. Recovery of renal function will often correct the hyperphosphatemia in the patient within 12 hours erectile dysfunction drugs and infertility discount sildalist 120 mg. Saline and/or acetazolamide (15 mg/kg q4h) can be given to further encourage phosphaturia cough syrup causes erectile dysfunction generic 120 mg sildalist, if needed. Hemodialysis may be required, especially if irreversible renal insufficiency or symptomatic hypocalcemia is present. Chronic hyperphosphatemia is almost always associated with chronic kidney disease. Its management consists of reducing phosphorus intake through dietary modification and the use of phosphate binders. Hypophosphatemia may be caused by (a) impaired intestinal absorption, (b) increased renal excretion, or (c) transcellular shift into cells. Often, there are several mechanisms that work in concert to lower serum phosphate. Impaired intestinal absorption occurs with the malabsorption syndromes, the use of oral phosphate binders, or vitamin D deficiency from any cause (see Calcium, Hypocalcemia, Etiology section). Chronic alcoholism is often associated with poor intake of both phosphate and vitamin D, resulting in total body phosphorus depletion. Hypophosphatemia may also occur from osmotic diuresis and disorders of proximal tubular transport such as familial X-linked hypophosphatemic rickets and Fanconi syndrome. The latter is responsible for the paradoxical reduction in phosphorus during treatment of malnutrition with hyperalimentation (the refeeding syndrome). The endogenous increase in insulin during treatment shifts phosphorus intracellularly, further reducing serum phosphorus in the malnourished individual. Phosphorus can also be rapidly absorbed into bone following parathyroidectomy for severe hyperparathyroidism (hungry bone syndrome). These end-organ effects are due to the inability to form adenosine triphosphate and the impaired tissue oxygen delivery that occurs with a decrease in red blood cell 2,3diphosphoglycerate. These include muscle injury (rhabdomyolysis, impaired diaphragmatic function, and heart failure), neurologic abnormalities (paresthesias, dysarthria, confusion, stupor, seizures, and coma), and rarely, hemolysis and platelet dysfunction. Diagnostic Testing the cause is usually apparent from the clinical situation in which the hypophosphatemia occurs. Renal excretion of >100 mg by 24-hour urine collection or a fractional excretion of phosphate >5% during hypophosphatemia indicates excessive renal loss. Because of the need to replenish intracellular stores, 24-36 hours of phosphate administration may be required. Extreme care must be used to avoid hyperphosphatemia, which may lead to hypocalcemia. If hypotension occurs, acute hypocalcemia should be suspected, and the infusion should be stopped or slowed. Further doses should be based on symptoms and on the serum calcium and phosphorus levels, which should be measured every 8 hours. Vitamin D deficiency, if present, should be treated first (see Calcium, Hypocalcemia, Treatment section) followed by oral supplementation of 0. Preparations include Neutra-Phos (250 mg elemental phosphorus and 7 mEq of Na+ and K+ per capsule) and Neutra-Phos K+ (250 mg elemental phosphorus and 14 mEq K+ per capsule). Fleet Phospho-Soda (815 mg phosphorus and 33 mEq sodium per 5 mL) is an alternative oral agent. Approximately 60% of body magnesium is stored in bone, and most of the remainder is found in cells. As a result, the serum magnesium is a poor predictor of intracellular and total body stores and may grossly underestimate total magnesium deficits. The main determinant of magnesium balance is the magnesium concentration itself, which directly influences renal excretion. Hypomagnesemia stimulates tubular reabsorption of magnesium, whereas hypermagnesemia inhibits it. Because renal excretion is the only means of lowering serum magnesium levels, the presence of significant renal insufficiency can lead to magnesium toxicity even with therapeutic doses of these antacids and laxatives. Neuromuscular abnormalities usually include hyporeflexia (usually the first sign of magnesium toxicity), lethargy, and weakness that can progress to paralysis and diaphragmatic involvement, leading to respiratory failure. In the setting of significant renal insufficiency, the inadvertent administration of magnesiumcontaining medications. In the setting of normal renal function, normal magnesium levels will quickly be attained with removal of the magnesium load. Symptomatic hypermagnesemia Prompt supportive therapy is critical, including mechanical ventilation for respiratory failure and a temporary pacemaker for significant bradyarrhythmias. With significant renal insufficiency, hemodialysis is required for definitive therapy. Hypomagnesemia is most commonly caused by impaired intestinal absorption and increased renal excretion. Decreased intestinal absorption occurs in malnutrition, as is common in chronic alcoholics or any malabsorption syndrome. Several medications similarly induce defects in tubular magnesium transport including aminoglycosides, amphotericin B, cisplatin, pentamidine, and cyclosporine. Atrial and ventricular arrhythmias may occur, especially in patients treated with digoxin. Diagnostic Testing Low serum [Mg2+] in conjunction with an appropriate clinical scenario is sufficient to establish the diagnosis of magnesium deficiency. However, due to the slow exchange of magnesium between the bone and intracellular pools (see Magnesium section), a normal serum level does not exclude total body magnesium deficiency. The etiology of hypomagnesemia usually is evident from the clinical context, but if there is uncertainty, measurement of urine magnesium excretion is helpful. A 24-hour urine magnesium of >2 mEq (or >24 mg) or a fractional excretion of magnesium of P. However, magnesium must be given with extreme care in the presence of renal insufficiency. The route of magnesium administration depends on whether clinical manifestations from magnesium deficiency are present. Numerous preparations exist, including Mag-Ox 400 (240 mg elemental magnesium per 400-mg tablet), UroMag (84 mg per 140-mg tablet), and sustained-release Slow-Mag (64 mg per tablet). Typically, approximately 240 mg of elemental magnesium is administered daily for mild deficiency, whereas more severe hypomagnesemia may require up to 720 mg/d of elemental magnesium. Normalization of serum magnesium levels can be deceiving, because the administered magnesium slowly shifts to replete intracellular and bone stores. Thus, serum levels should be followed closely, and replacement should be maintained until patients demonstrate stable normalization of serum magnesium concentrations. To account for gradual redistribution to severely depleted intracellular stores, replacement therapy may need to be maintained, often for 3-7 days. Serum magnesium should be measured daily and the infusion rate adjusted to maintain a serum magnesium level of <2. Tendon reflexes should be tested frequently, because hyporeflexia suggests hypermagnesemia. Reduced doses and more frequent monitoring must be used even in mild renal insufficiency. Acidemia and alkalemia refer to processes that lower and raise pH regardless of mechanism. Once the acid-base process is correctly identified, further diagnostic studies may be undertaken to determine the precise etiologies at play. The compensatory mechanism is an adaptation to the primary acid-base disturbance intended to stabilize the changing pH. A respiratory process that shifts the pH in one direction will be compensated by a metabolic process that shifts the pH in the other and vice versa. The effect of compensation is to attenuate, but not completely correct, the primary change in pH. The expected compensations for the various primary acid-base derangements are given in Table 12-2. An inappropriate compensatory response suggests the presence of a combined disorder. In normal individuals, the total serum cations are balanced with the total serum anions. Example: A patient is admitted with fevers and hypotension after a prolonged course of diarrhea. Urinary buffers reduce the concentration of free H+ in the filtrate, thus attenuating the back leak of H+, which occurs at low urinary pH. Causes include inherited mutations (cystinosis), heavy metals, drugs (tenofovir, ifosfamide, carbonic anhydrase inhibitors), and multiple myeloma and other monoclonal gammopathies. It can also be caused by a back leak of H+ due to increased membrane permeability, as seen with amphotericin B. Hyporeninemic hypoaldosteronism is seen with some frequency in patients with diabetes. Occasionally, the kidney is unable to secrete sufficient H+ due to an impaired luminal gradient. In these situations, poor filtrate delivery or impaired Na+ reabsorption in the distal nephron is responsible for decreasing the voltage gradient, which augments H+ secretion. This can be seen with marked volume depletion, urinary tract obstruction, sickle cell nephropathy, and amiloride or triamterene use. The specific cause of an elevated anion gap can usually be determined by clinical history. However, specific laboratory studies are available to identify certain anions such as lactate, acetoacetate, acetone, and -hydroxybutyrate. Clinical suspicion for toxic alcohol ingestion is corroborated by an increased osmolal gap. Types 1 and 2 are typically associated with hypokalemia, whereas type 4 is characterized by hyperkalemia. It is elevated during the initial bicarbonaturia, when filtered bicarbonate exceeds the threshold for reabsorption, and low when the filtered load is below this threshold. Lactic acidosis will resolve once the underlying cause is treated and tissue perfusion is restored. Often, this involves aggressive therapeutic maneuvers for the treatment of shock as described in Chapter 8, Critical Care. Correction of the chronic acidemia with alkali administration is warranted in order to prevent its catabolic effect on bone and muscle. Potassium citrate replacement may be necessary for patients with hypokalemia, nephrolithiasis, or nephrocalcinosis. Administration of potassium salts minimizes the degree of hypokalemia associated with alkali therapy. Contraction alkalosis refers to the contraction of volume around a fixed content of bicarbonate. Metabolic alkalosis is often described as being chloride responsive or chloride unresponsive. Urine electrolytes are generally useful in identifying the etiology of a metabolic alkalosis when the history and physical are unrevealing. A urine [Cl-] <20 mEq/L is consistent with chloride-responsive metabolic alkalosis and usually indicates volume depletion. Urine [Na+] is not reliable in predicting the effective circulating volume in these conditions, because bicarbonaturia obligates renal Na+ loss even in volume depletion. Serum potassium levels are often low in metabolic alkalosis due to transcellular shifts. Furthermore, hypokalemia contributes to alkalosis by increasing tubular H+ secretion and Cl- wasting. The increase in filtered chloride leads to improved renal handling of the bicarbonate load. Mineralocorticoid excess can be managed with a K+-sparing diuretic (amiloride or spironolactone) and repletion of the K+ deficit. Given that the presence of hypokalemia will continue to perpetuate some degree of alkalosis regardless of other interventions, potassium must be repleted in all cases of metabolic alkalosis. A very severe hypercapnia may be well tolerated if it is accompanied by renal compensation and a relatively normal pH. Initial symptoms and signs may include headache and restlessness, which may progress to generalized hyperreflexia/asterixis and coma. Symptoms and signs of acute hypocalcemia (see Calcium, Hypocalcemia, Clinical Presentation section) may be evident from the abrupt fall in ionized calcium that can occur. Chronic respiratory alkalosis is usually asymptomatic because a normal pH is well defended by compensation. Diagnostic Testing the rise in pH from acute respiratory alkalosis can cause a reduced ionized calcium, a profound hypophosphatemia, and hypokalemia. In intensive care unit patients, this may involve changing the ventilator settings to decrease ventilation (see Chapter 8, Critical Care). Its presence is frequently first noted on abnormal routine laboratory data, generally as an elevated serum creatinine (Cr) level.

Patients on high doses (>2-3 mg/kg/min) or those with renal dysfunction should have serum levels of thiocyanate drawn after 48-72 hours of therapy relative impotence judiciary generic sildalist 120 mg amex. In patients with normal renal function or those receiving lower doses erectile dysfunction treatment homeopathy purchase genuine sildalist line, levels can be drawn after 5-7 days next generation erectile dysfunction drugs buy sildalist 120mg visa. Hepatic dysfunction may result in accumulation of cyanide erectile dysfunction more causes risk factors purchase 120mg sildalist with mastercard, which can cause metabolic acidosis erectile dysfunction diabetes generic 120mg sildalist with mastercard, dyspnea erectile dysfunction main causes sildalist 120 mg with amex, vomiting, dizziness, ataxia, and syncope. It is the preferred agent for patients with moderate hypertension in the setting of acute coronary ischemia or after coronary artery bypass surgery because of its more favorable effects on pulmonary gas exchange and collateral coronary blood flow. When given intravenously, the adrenergic antagonist effect is greater than the -adrenergic antagonist effect. Esmolol is a parenteral, short-acting, cardioselective -adrenergic antagonist (see Table 3-5) that can be used in the treatment of hypertensive emergencies in patients in whom -blocker intolerance is a concern. Side effects include headache, flushing, reflex tachycardia, and venous irritation. Fifty percent of the peak effect is seen within the first 30 minutes, but the full peak effect is not achieved until after 48 hours of administration. Enalaprilat is the active de-esterified form of enalapril (see Table 3-5) that results from hepatic conversion after an oral dose. Diazoxide and hydralazine are only rarely used in hypertensive crises and offer little or no advantage to the agents discussed previously. It should be noted, however, that hydralazine is a useful agent in pregnancy-related hypertensive emergencies because of its established safety profile. Fenoldopam is a selective agonist to peripheral dopamine-1 receptors, and it produces vasodilation, increases renal perfusion, and enhances natriuresis. Fenoldopam has a short duration of action; the elimination half-life is <10 minutes. The drug has important application as parenteral therapy for high-risk hypertensive surgical patients and the perioperative management of patients undergoing organ transplantation. After 6 hours, a diuretic can be added, and an 8-hour clonidine dosing interval can be begun. A reasonable goal is a 20-25% reduction of mean arterial pressure or a reduction of the diastolic pressure to 100-110 mm Hg over a period of minutes to hours. Aortic dissection Acute proximal aortic dissection (type A) is a surgical emergency, whereas uncomplicated distal dissection (type B) can be treated successfully with medical therapy alone. All patients, including those treated surgically, require acute and chronic antihypertensive therapy to provide initial stabilization and to prevent complications. Antihypertensive agents with negative inotropic properties, including calcium channel antagonists, -adrenergic antagonists, methyldopa, clonidine, and reserpine, are preferred for management in the postacute phase. Sodium nitroprusside is considered the initial drug of choice because of the predictability of response and absence of tachyphylaxis. Nitroprusside alone causes an increase in left ventricular contractility and subsequent arterial shearing forces, which contribute to ongoing intimal dissection. Thus, when using sodium nitroprusside, adequate simultaneous -adrenergic antagonist therapy is essential, regardless of whether systolic hypertension is present. Esmolol, a cardioselective class intravenous -adrenergic antagonist with a very short duration of action, may be preferable, especially in patients with relative contraindications to -antagonists. It has the advantage of allowing for oral administration after the acute stage of dissection has been managed successfully. Often, elderly hypertensive patients have coexisting medical problems that must be considered when initiating antihypertensive therapy. Calcium channel antagonists decrease vascular resistance, have no adverse effects on lipid levels, and are also good choices for elderly patients. Thus, African American patients respond well to diuretics, alone or in combination with calcium channel antagonists. The obese hypertensive patient is characterized by more modest elevations in vascular resistance, higher cardiac output, expanded intravascular volume, and lower plasma renin activity at any given level of arterial pressure. The diabetic patient with nephropathy may have significant proteinuria and renal insufficiency, which can complicate management (see Chapter 13, Renal Diseases). The patient with chronic renal insufficiency has hypertension that usually is partially volume dependent. Retention of sodium and water exacerbates the existing hypertensive state, and diuretics are important in the management of this problem. Nondihydropyridine calcium channel antagonists should generally be avoided in patients in whom negative inotropic effects would affect their status adversely. The possibility of teratogenic or other adverse effects of antihypertensive medications on fetal development also should be considered. Classification of hypertension during pregnancy has been proposed by the American College of Obstetrics and Gynecology (Obstet Gynecol 2013;122(5):1122). Diagnosis is established if there is new-onset hypertension after 20 weeks of gestation and the presence of proteinuria. If no proteinuria is present, then hypertension along with one of the following qualifies: platelets <100,000/L, creatinine >1. This classification is used when a woman with chronic hypertension develops worsening hypertension and new proteinuria and/or other features of preeclampsia as outlined previously. Nonpharmacologic therapy, such as weight reduction and vigorous exercise, is not recommended during pregnancy. Pharmacologic intervention with labetalol, nifedipine, or methyldopa is recommended as first-line therapy because of its proven safety. If a patient is suspected of having preeclampsia or eclampsia, urgent referral to an obstetrician who specializes in high-risk pregnancy is recommended. Interactions are common with tricyclic antidepressants, meperidine, methyldopa, levodopa, sympathomimetic agents, and antihistamines. Tyramine-containing foods that can lead to this syndrome include certain cheeses, red wine, beer, chocolate, chicken liver, processed meat, herring, broad beans, canned figs, and yeast. Discontinuation of antihypertensive medications should be done with caution in patients with preexisting cerebrovascular or P. Hypertension should not be diagnosed on the basis of one measurement alone, unless it is >210/120 mm Hg or accompanied by target organ damage. Two or more abnormal readings should be obtained, preferably over a period of several weeks, before therapy is considered. Care should also be used to exclude pseudohypertension, which usually occurs in elderly individuals with stiff, noncompressible vessels. A palpable artery that persists after cuff inflation (Osler sign) should alert the physician to this possibility. Plasma lipids are transported by lipoprotein particles composed of apolipoproteins, phospholipids, free cholesterol, cholesterol esters, and triglycerides. Differential diagnosis of the major lipid abnormalities is summarized in Table 3-7. The major genetic dyslipoproteinemias are reviewed in Table 3-8 (Circulation 1974;49:476; J Lipid Res 1990;31:1337; Clin Invest 1993;71:362). Familial hypercholesterolemia and familial combined hyperlipidemia are disorders that contribute significantly to premature cardiovascular disease. It is associated with significantly increased risk of early cardiovascular disease when untreated (J Clin Lipidol 2011;5:133). Familial combined hyperlipidemia has a prevalence of 1-2% and typically presents in adulthood, although obesity and high dietary fat and sugar intake have led to increased presentation in childhood and adolescence (J Clin Endocrinol Metab 2012;97:2969). These guidelines address risk assessment (Circulation 2014;129:S49), lifestyle modifications (Circulation 2014;129:S76), evaluation and treatment of obesity (Circulation 2014;129:S102), and evaluation and management of blood cholesterol (Circulation 2014;129:S1). Patients hospitalized for an acute coronary syndrome or coronary revascularization should have a lipid panel obtained within 24 hours of admission if lipid levels are unknown. For patients of ethnicities other than African American or non-Hispanic white, risk cannot be as well assessed. Use of the non-Hispanic white risk calculation is suggested, with the understanding that risk may be lower than calculated in East Asian Americans and Hispanic Americans and higher in American Indians and South Asians. Lifetime risk may be calculated in patients age 20-39 and patients age 40-59 with a 10-year risk <7. Patients should be advised to adopt a diet that is high in fruits and vegetables, whole grains, fish, lean meat, low-fat dairy, legumes, and nuts, with lower intake of red meat, saturated and trans fats, sweets, and sugary beverages (Table 3-9). Saturated fat should comprise no more than 5-6% of total calories (Circulation 2014;129:S76). Physical activity, including aerobic and resistance exercise, is recommended in all patients (Circulation 2014;129:S76). Consultation with a registered dietitian may be helpful to plan, start, and maintain a saturated fat-restricted and weight loss-promoting diet. Prior to the start of treatment, there should be a risk discussion between the patient and the clinician. Secondary prevention is an indication for high-intensity statin therapy, which has been shown to reduce events more than moderate-intensity statin therapy. If high-dose statin therapy is contraindicated or poorly tolerated or there are significant risks to high-intensity therapy (including age >75 years), moderate-intensity therapy is an option. If high-intensity therapy is not tolerated, maximum tolerated intensity should be used. Because hyperlipidemia of this degree is often genetically determined, discuss screening of other family members (including children) to identify candidates for treatment. In addition, screen for and treat secondary causes of hyperlipidemia (Curr Opin Lipidol 2012;23:282). Otherwise, these patients have an indication for moderate-intensity statin therapy. The decision between moderate- and highintensity therapy should be made with the patient based on anticipated individualized risks and benefits. Patients with diabetes younger than 40 or older than 75 are reasonable candidates for statin therapy based on individual evaluation. In randomized controlled trials, patients older than 75 continued to have benefit from statin therapy, particularly for secondary prevention (Lancet 2002;360:7; Lancet 2002;360:1623). Evidence from randomized controlled trials has not shown a benefit from statin therapy in these subpopulations (Circulation 2014;129:S1). Hypertriglyceridemia Hypertriglyceridemia may be an independent cardiovascular risk factor (Circulation 2007;115:450; Ann Intern Med 2007;147:377; Circulation 2011;123:2292). The Endocrine Society has added two further categories: severe: 1000-1999 mg/dL (greatly increases the risk of pancreatitis); and very severe: 2000 mg/dL (J Clin Endocrinol Metab 2012;97:2969). For patients with very high triglyceride levels, triglyceride reduction through a very low-fat diet (15% of calories), exercise, weight loss, and drugs (fibrates, niacin, -3 fatty acids) is the primary goal of therapy to prevent acute pancreatitis. Lifestyle changes are indicated to lower triglyceride levels (J Clin Endocrinol Metab 2012;97:2969). A repeat fasting lipid panel is indicated 4-12 weeks after starting therapy to assess adherence, with reassessment every 3-12 months as indicated. In contrast to previous guidelines, therapeutic targets are not recommended because specific targets and a "treat to target" strategy have not been evaluated in randomized controlled trials. After evaluation, if the therapeutic response is still insufficient on maximally tolerated statin therapy, it is reasonable to consider adding a nonstatin agent. Creatine kinase should not be routinely checked in patients on statin therapy but is reasonable to measure in patients with muscle symptoms. The lipid-lowering effect of statins appears within the first week of use and becomes stable after approximately 4 weeks of use. Other potential side effects include malaise, fatigue, headache, and rash (N Engl J Med 1999;341:498; Ann Pharmacother 2002;36:1907; Circulation 2002;106:1024). Myalgias are the most common cause of statin discontinuation and are often dose dependent. They occur more often with increasing age and number of medications and decreasing renal function and body size (Circulation 2002;106:1024; Endocrinol Metab Clin North Am 2009;38:121). For mild to moderate symptoms, evaluate for conditions increasing the risk of muscle symptoms, including renal or hepatic impairment, hypothyroidism, vitamin D deficiency, rheumatologic disorders, and primary muscle disorders. Statin-induced myalgias are likely to resolve within 2 months of discontinuing the drug. If symptoms recur, use a low dose of a different statin and increase as tolerated. If the cause of symptoms is determined to be unrelated, restart the original statin. However, the total benefit of statin use usually outweighs the potential adverse effects from an increase in blood sugar (Lancet 2010;375:735). Statins have very rarely been associated with reversible cognitive impairment and have not been associated with irreversible or progressive dementia. Because some of the statins undergo metabolism by the cytochrome P450 enzyme system, taking these statins in combination with other drugs metabolized by this enzyme system increases the risk of rhabdomyolysis (N Engl J Med 1999;341:498; Ann Pharmacother 2002;36:1907; Circulation 2002;106:1024). Among these drugs are fibrates (greater risk with gemfibrozil), itraconazole, ketoconazole, erythromycin, clarithromycin, cyclosporine, nefazodone, and protease inhibitors (Circulation 2002;106:1024). Statins may also interact with large quantities of grapefruit juice to increase the risk of myopathy. Simvastatin can increase the levels of warfarin and digoxin and has significant doselimiting interactions with amlodipine, amiodarone, dronedarone, verapamil, diltiazem, and ranolazine. Because a number of drug interactions are possible depending on the statin and other medications being used, drug interaction programs and package inserts should be consulted (J Clin Lipidol 2014;8:S30). These agents should not be used as monotherapy in patients with triglyceride levels >250 mg/dL because they can raise triglyceride levels. Common side effects of resins include constipation, abdominal pain, bloating, nausea, and flatulence. Bile acid sequestrants may decrease oral absorption of many other drugs, including warfarin, digoxin, thyroid hormone, thiazide diuretics, amiodarone, glipizide, and statins. Colesevelam interacts with fewer drugs than do the older resins but can affect the absorption of thyroxine. Common side effects of niacin include flushing, pruritus, headache, nausea, and bloating.

Subsequently impotence at 16 buy 120mg sildalist overnight delivery, blood vessels at the margins of the wheal dilate and become engorged with red blood cells reflexology erectile dysfunction treatment buy 120 mg sildalist otc, producing a characteristic red rim called a flare erectile dysfunction treatment japan discount sildalist 120mg visa. The full wheal-and-flare reaction can appear within 5 to 10 minutes after administration of antigen and usually subsides in less than 1 hour johns hopkins erectile dysfunction treatment order 120 mg sildalist mastercard. Histologic examination shows that mast cells in the area of the wheal-and-flare have released preformed mediators; that is erectile dysfunction causes yahoo generic sildalist 120 mg online, their cytoplasmic granules have been discharged erectile dysfunction treatment over the counter discount 120 mg sildalist otc. A causal association of IgE and mast cells with immediate hypersensitivity was first deduced from experiments involving the passive transfer of IgE antibodies from an allergic individual into a normal recipient. For example, immediate hypersensitivity reactions against an allergen can be elicited in unresponsive individuals if the local skin site is first injected with IgE from an allergic individual. Such adoptive transfer experiments were first performed with serum from immunized individuals, and the serum factor responsible for the reaction was originally called reagin. The antigen-initiated skin reaction that follows adoptive transfer of IgE is called passive cutaneous anaphylaxis. Skin mast cells appear to produce only small amounts of long-acting mediators such as leukotrienes, so the wheal-and-flare response subsides rapidly. Allergists often test patients for allergies to different antigens by examining the ability of these antigens applied in skin patches or administered through small needle pricks to elicit wheal-and-flare reactions. The Late-Phase Reaction the immediate wheal-and-flare reaction is followed 2 to 4 hours later by a late-phase reaction consisting of the accumulation of inflammatory leukocytes, including neutrophils, eosinophils, basophils, and helper T cells. The types of leukocytes that are typical of late-phase reactions are eosinophils and helper T cells. Bronchial asthma is a disease in which there may be repeated bouts of inflammation with accumulations of eosinophils and Th2 cells without the vascular changes that are characteristic of the immediate response. In such disorders, there may be little mast cell activation, and the cytokines that sustain the late-phase reaction may be produced mainly by T cells. A, In a clinical test for allergies, different antigens are introduced into the skin by short needles. Patients with allergies to an antigen will have antigen-specific IgE already bound to mast cells in the skin and the mast cells will be activated. In response to antigen-stimulated release of mast cell mediators, local blood vessels first dilate and then become leaky to fluid and macromolecules, which produces redness and local swelling (a wheal). Subsequent dilation of vessels on the edge of the swelling produces the appearance of a red rim (the flare). B, Photograph of a typical allergy positive skin test showing wheal-and-flare reactions in the skin in response to injection of allergens. Abnormally high levels of IgE synthesis and associated atopy often run in families. Family studies have shown clear autosomal transmission of atopy, although the full inheritance pattern is multigenic. Thus, allergic rhinitis (hay fever), asthma, and atopic dermatitis (eczema) can be present to various degrees in different members of the same kindred. Various approaches have been taken to identify genes that carry a risk for allergic diseases, including positional cloning, candidate gene studies, and genome-wide association studies. These approaches have identified many different gene variants that confer increased susceptibility for asthma and other atopic diseases (Table 20. Based on the known functions of the proteins encoded by many of these genes, rational speculations can be made about how altered expression or activity of these proteins might impact the development or severity of allergic diseases. Nonetheless, we still know very little about whether or not the genetic polymorphisms that are associated with increased risk for allergy actually alter expression or function of the encoded proteins, and, in many cases, it is not clear how the function of many of the encoded proteins could impact the development of allergy. This region is of great interest because of the connection between several genes located there and the mechanisms of IgE regulation and mast cell and eosinophil growth and differentiation. As mentioned earlier, filaggrin is required for skin barrier functions and water retention, and a lack of this protein is thought to promote keratinocyte damage and cytokine release, as well as allergen entry into the dermis. Some genes whose products regulate the innate immune response to infections have been associated with allergy and asthma. Because innate responses to many infections generally favor development of Th1 responses and inhibit Th2 responses (see Chapter 10), it is possible that polymorphisms or mutations in genes that result in enhanced or diminished innate responses to common infectious organisms may influence the risk for development of atopy. Other genome-wide association studies have found significant associations of common variants of numerous other genes with asthma and other atopic diseases. However, either the products of these genes are of unknown function, or the connection between their known functions and the development of atopic disease is not known. Environmental Factors in Allergy It is clear that environmental influences have a significant impact on the development of allergy, and they synergize with genetic risk factors. Environmental influences include exposure to allergens themselves, to infectious organisms, and possibly other factors that impact mucosal barrier function, such as air pollution. Furthermore, the time of life when exposure to these environmental factors occurs, especially early-life exposure, appears to be important. Exposure to microbes during early childhood may reduce the risk for developing allergies. One possible explanation for the increased prevalence of asthma and other atopic diseases in industrialized countries is that the frequency of infections in these countries is generally lower. Based on these data, the hygiene hypothesis was proposed, which states that early-life and even perinatal exposure to gut commensals and infections leads to a regulated maturation of the immune system, and perhaps early development of regulatory T cells. As a result, later in life these individuals are less likely to mount Th2 responses to noninfectious environmental antigens and less likely to develop allergic diseases. Respiratory viral and bacterial infections are a predisposing factor in the development of asthma or exacerbations of preexisting asthma. For example, it is estimated that respiratory viral infections precede up to 80% of asthma attacks in children. This may seem contradictory to the hygiene hypothesis, but these asthma-associated infections are due to human pathogens that may damage pulmonary mucosal barriers, while the data supporting the hygiene hypothesis focus on exposure to a broad range of environmental bacteria not necessarily related to tissue injury. Atopic individuals may have one or more types of allergy, the most common forms being allergic rhinitis, bronchial asthma, atopic dermatitis, and food allergies. The clinical and pathologic features of allergic reactions vary with the anatomic site of the reaction, for several reasons. The point of contact with the allergen can determine the organs or tissues where mast cells and Th2 cells are activated. For example, inhaled antigens cause rhinitis or asthma, ingested antigens often cause vomiting and diarrhea (but can also produce skin and respiratory symptoms if larger doses are ingested), and injected antigens cause systemic effects on the circulation. The concentration of mast cells in various target organs influences the severity of responses. Mast cells are particularly abundant in the skin and the mucosa of the respiratory and gastrointestinal tracts, and these tissues frequently suffer the most injury in immediate hypersensitivity reactions. The local mast cell phenotype may influence the characteristics of the immediate hypersensitivity reaction. For example, connective tissue mast cells produce abundant histamine and are responsible for wheal-and-flare reactions in the skin. In the following section, we will discuss the major features of allergic diseases manifested in different tissues. These effects usually result from the systemic presence of antigen introduced by injection, an insect sting, or absorption across an epithelial surface such as gut mucosa. The allergens that most often cause anaphylaxis include penicillin family antibiotics, and proteins in peanuts, tree nuts, fish, shellfish, milk, eggs, and bee venom, but there are many other drug, food, and environmental culprits. The allergen activates mast cells in many tissues, resulting in the release of mediators that gain access to vascular beds throughout the body. The decrease in vascular tone and leakage of plasma caused by mast cell mediators can lead to a significant decrease in blood pressure, or shock, called anaphylactic shock, which is often fatal. Mast cell mediators may impair breathing by causing laryngeal edema, bronchoconstriction and excess bronchial mucus production. There is often diarrhea due to intestinal hypermotility and outpouring of mucus in the gut, and urticarial lesions (hives) in the skin. In about 20% of patients a second recurrence of symptoms is seen without known reexposure to the allergen, up to 12 hours after the first episode. This is often called a latephase anaphylactic reaction but should not be confused with the late-phase response to allergen discussed earlier. It is not known which mast cell mediators are the most important in anaphylactic shock. The mainstay of treatment is systemic epinephrine, which can be lifesaving by reversing the bronchoconstrictive and vasodilatory effects of mast cell mediators. Epinephrine also improves cardiac output, further aiding survival from threatened circulatory collapse. Antihistamines may also be beneficial in anaphylaxis, suggesting a role for histamine in this reaction. Bronchial Asthma Asthma includes a group of pulmonary diseases characterized by recurrent reversible airflow obstruction and bronchial smooth muscle cell hyperresponsiveness, which is most often caused by repeated immediate-type hypersensitivity and late-phase allergic reactions. Patients suffer paroxysms of bronchoconstriction and increased production of thick mucus, which lead to bronchial obstruction and respiratory difficulties. Asthma in adults frequently coexists with chronic obstructive pulmonary disease, and the combination of these diseases can cause severe irreversible airflow obstruction. Asthma affects approximately 20 million people in the United States, and the frequency of this disease has increased significantly over the past 30 to 40 years. The prevalence rate is similar to that in other industrialized countries, but it may be lower in less developed areas of the world. Approximately 70% of cases of asthma are associated with IgE-mediated reactions reflecting atopy. In the remaining 30% of patients, asthma may be triggered by nonimmune stimuli, such as drugs, cold, and exercise. Atopic bronchial asthma results from repeated immediate hypersensitivity reactions in the lungs with chronic late-phase reactions. A crosssection of a normal bronchus (A) and a cross-section of a bronchus from a patient with asthma (B) are shown. The pathophysiologic sequence in atopic asthma is probably initiated by mast cell activation in response to allergen binding to IgE, as well as by Th2 cells reacting to allergens. The lipid mediators and cytokines produced by the mast cells and T cells lead to the recruitment of eosinophils, basophils, and more Th2 cells. The chronic inflammation in this disease may continue without mast cell activation. Smooth muscle cell hypertrophy and hyperreactivity are thought to result from leukocyte-derived mediators and cytokines. Mast cells, basophils, and eosinophils all produce mediators that constrict airway smooth muscle. The most important of the bronchoconstricting mediators are cysteinyl leukotrienes. Current therapy for asthma has two major targets: prevention and reversal of inflammation and relaxation of airway smooth muscle. Several classes of drugs are in current use to treat asthma, but antiinflammatory agents are now the primary mode of treatment. Corticosteroids may also be given systemically, especially once an attack is under way, to reduce inflammation. Leukotriene receptor antagonists block the binding of bronchoconstricting leukotrienes to receptors on airway smooth muscle cells. A humanized monoclonal anti-IgE antibody is an approved therapy that effectively reduces serum IgE levels in patients. This is an excellent example of precision medicine, in which markers for type 2 responses are used to identify the patients most likely to benefit from therapy antagonizing a type 2 cytokine. Because histamine has little role in airway constriction, antihistamines (H1 receptor antagonists) are not useful in the treatment of asthma. Indeed, because many antihistamines are also anticholinergics, these drugs may worsen airway obstruction by causing thickening of mucus secretions. Therapy is targeted both at reducing mast cell activation with anti-IgE, mast cell degranulation with inhibitors such as cromolyn and at countering mediator actions on bronchial smooth muscle by leukotriene antagonists and bronchodilators such as inhaled -adrenergic receptor agonists. The pathologic and clinical manifestations include mucosal edema, leukocyte infiltration with abundant eosinophils, mucus secretion, coughing, sneezing, and difficulty in breathing. Focal protrusions of the nasal mucosa, called nasal polyps, filled with edema fluid and eosinophils may develop in patients who suffer frequent repetitive bouts of allergic rhinitis. The resulting clinical manifestations include pruritus, tissue edema, enhanced peristalsis, increased epithelial fluid secretion, and associated symptoms of oropharyngeal swelling, vomiting, and diarrhea. Rhinitis, urticaria, and mild bronchospasm are also often associated with allergic reactions to food, suggestive of systemic antigen exposure, and anaphylaxis may occasionally occur. Allergic reactions to many different types of food have been described; some of the most common are peanuts and shellfish. Individuals may be sufficiently sensitive to these allergens that severe systemic reactions can occur in response to small accidental ingestions. Because the reaction that ensues is mediated largely by histamine, antihistamines can attenuate this response and are the mainstay of therapy. Atopic dermatitis (commonly called eczema) is part of the atopic triad (atopic dermatitis, allergic rhinitis, and asthma) but can also occur in isolation.

Adaptive Immunity to Extracellular Bacteria Humoral immunity is a major protective immune response against extracellular bacteria erectile dysfunction otc meds buy sildalist now, and it functions to block infection erectile dysfunction doctors raleigh nc generic 120mg sildalist visa, to eliminate the microbes impotence curse buy sildalist pills in toronto, and to neutralize their toxins erectile dysfunction treatment in dubai sildalist 120mg without a prescription. Helper T cells produce cytokines that stimulate inflammation impotence of organic origin meaning proven sildalist 120 mg, macrophage activation erectile dysfunction treatment in usa purchase sildalist master card, and B cell responses. The polysaccharides are T-independent antigens that elicit antibody responses but do not activate T cells. Therefore, humoral immunity is the principal mechanism of defense against polysaccharide-rich encapsulated bacteria. For these microbes, including Streptococcus pneumonia, Neisseria species, and others, the spleen plays a major role in both production of the antibodies and the phagocytic clearance of the opsonized bacteria. People who lose their spleens due to trauma or hematologic disorders are at great risk for severe infections by these encapsulated bacteria. Protein antigens, which are present in or secreted by most bacteria, elicit more potent antibodies, as well as cell-mediated immunity. The effector mechanisms used by antibodies to combat infections include neutralization, opsonization and phagocytosis, and activation of complement by the classical pathway (see Chapter 13). Neutralization is mediated by highaffinity IgG, IgM, and IgA isotypes, the latter mainly in the lumens of mucosal organs. Opsonization is mediated by the IgG1 and IgG3 subclasses of IgG, and complement activation is initiated by IgM, IgG1, and IgG3. Th17 responses induced by these microbes recruit neutrophils and monocytes and thus promote local inflammation at sites of bacterial infection. This early burst of large amounts of cytokines is sometimes called a cytokine storm. Their importance lies in their ability to activate many T cells, with the subsequent production of large amounts of cytokines that can also cause a systemic inflammatory syndrome. A late complication of the humoral immune response to bacterial infection may be the generation of diseaseproducing antibodies. The best defined examples are two rare sequelae of streptococcal infections of the throat or skin that are manifested weeks or even months after the infections are controlled. Rheumatic fever is a sequel to pharyngeal infection with some serologic types of group A -hemolytic streptococci. Infection leads to the production of antibodies against a bacterial cell wall protein. Some of these antibodies cross-react with myocardial proteins and are deposited in the heart, where they cause inflammation (carditis). Post-streptococcal glomerulonephritis is a sequel to infection of the skin or throat with "nephritogenic" serotypes of group A -hemolytic streptococci. Antibodies produced against these bacteria form complexes with bacterial antigen, which may be deposited in kidney glomeruli and cause nephritis. Injurious Effects of Immune Responses to Extracellular Bacteria the principal injurious consequences of host responses to extracellular bacteria are inflammation and sepsis. The same reactions of neutrophils and macrophages that function to eradicate the infection also cause tissue damage by local production of reactive oxygen species and lysosomal enzymes. Cytokines secreted by leukocytes in response to bacterial products also stimulate the production of acute-phase proteins and cause the systemic manifestations of the infection (see Chapter 4). Sepsis is a pathologic consequence of severe infection by some gram-negative and gram-positive bacteria (as well as some fungi), in which viable microbes or microbial products are present in the blood. These cause systemic disorders of tissue perfusion, coagulation, metabolism, and organ function. Septic shock is the most severe and frequently fatal form of sepsis, characterized by circulatory collapse (shock) and disseminated intravascular Immune Evasion by Extracellular Bacteria the virulence of extracellular bacteria has been linked to a number of mechanisms that enable the microbes to resist innate immunity (Table 16. Bacteria with polysaccharide-rich capsules resist phagocytosis and are therefore more virulent than homologous strains lacking a capsule. The capsules of many pathogenic gram-positive and gram-negative bacteria contain sialic acid residues that inhibit complement activation by the alternative pathway. A mechanism used by bacteria to evade humoral immunity is variation of surface antigens. Some surface antigens of bacteria, such as gonococci and Escherichia coli, are contained in their pili, which are the structures responsible for bacterial adhesion to host cells. The pilin genes of gonococci undergo extensive gene conversion, because of which the progeny of one organism can produce up to 106 antigenically distinct pilin molecules. Bacteria also release surface antigens in membrane blebs, which may divert antibodies away from the microbes themselves. Because these microbes are able to find a niche where they are inaccessible to circulating antibodies, their elimination requires the mechanisms of cell-mediated immunity. As we will discuss later in this section, in many intracellular bacterial infections the host response also causes tissue injury. Phagocytes, initially neutrophils and later macrophages, ingest and attempt to destroy these microbes, but pathogenic intracellular bacteria are resistant to degradation within phagocytes. Shown are the multiple mechanisms used by one bacterial species, Neisseria, to evade humoral immunity. However, innate immunity usually fails to eradicate these infections, and eradication requires adaptive cell-mediated immunity. Many of the important features of cell-mediated immunity were established in the 1950s based on studies of immune responses to the intracellular bacterium L. This form of immunity could be adoptively transferred to naive animals with lymphoid cells but not with serum from infected or immunized animals. The typical adaptive immune response to these microbes is cell-mediated immunity, in which T cells activate phagocytes to eliminate the microbes. Innate immunity may control bacterial growth, but elimination of the bacteria requires adaptive immunity. These principles are based largely on analysis of Listeria monocytogenes infection in mice; the numbers of viable bacteria shown on the y-axis are relative values of bacterial colonies that can be grown from the tissues of infected mice. The macrophage activation that occurs in response to intracellular microbes is capable of causing tissue injury. Because intracellular bacteria have evolved to resist killing within phagocytes, they often persist for long periods and cause chronic T cell and macrophage activation, which may result in the formation of granulomas surrounding the microbes. The histologic hallmark of infection with some intracellular bacteria is granulomatous inflammation. This type of inflammatory reaction may serve to localize and prevent spread of the microbes, but it is also associated with severe functional impairment caused by tissue necrosis and fibrosis. In fact, necrotizing granulomas and the fibrosis (scarring) that accompanies granulomatous inflammation are important causes of tissue injury and clinical disease in tuberculosis. Differences among individuals in the patterns of T cell responses to intracellular microbes are important determinants of disease progression and clinical outcome. Leprosy, which is caused by Mycobacterium leprae, is considered an example of the relationship between the type of T cell response and disease outcome in humans. There are two polar forms of leprosy, the lepromatous and tuberculoid forms, although many patients fall into less clear intermediate groups. In lepromatous leprosy, patients have high specific antibody titers but weak cellmediated responses to M. The bacterial growth and persistent but inadequate macrophage activation result in destructive lesions in the skin and underlying tissue. In contrast, patients with tuberculoid leprosy have strong cellmediated immunity but low antibody levels. This pattern of immunity is reflected in granulomas that form around nerves and produce peripheral sensory nerve defects and secondary traumatic skin lesions but with less tissue destruction and a paucity of bacteria in the lesions. One possible reason for the differences in these two forms of disease caused by the same organism may be that there are different patterns of T cell differentiation and cytokine production in individuals. The role of Th1and Th2-derived cytokines in determining the outcome of infection has been most clearly demonstrated in infection by the protozoan parasite Leishmania major in different strains of inbred mice (discussed later in this chapter). Immune Evasion by Intracellular Bacteria Intracellular bacteria have developed various strategies to resist elimination by phagocytes (see Table 16. These include inhibiting phagolysosome fusion or escaping into the cytosol, thus hiding from the microbicidal mechanisms of lysosomes, and directly scavenging or inactivating microbicidal substances, such as reactive oxygen species. Resistance to phagocyte-mediated elimination is also the reason that such bacteria tend to cause chronic infections that may last for years, often recur after apparent cure, and are difficult to eradicate. Some fungal Immunity to Fungi 361 infections are endemic, and these infections are usually caused by fungi that are present in the environment and whose spores enter humans. Other fungal infections are said to be opportunistic because the causative agents cause mild or no disease in healthy individuals but may infect and cause severe disease in immunodeficient persons. Compromised immunity is the most important predisposing factor for clinically significant fungal infections. Neutrophil deficiency as a result of bone marrow suppression or damage is frequently associated with such infections. Different fungi infect humans and may live in extracellular tissues and within phagocytes. Therefore, the immune responses to these microbes are often combinations of the responses to extracellular and intracellular microbes. However, less is known about antifungal immunity than about immunity against bacteria and viruses. This lack of knowledge is partly due to the paucity of animal models for mycoses and partly due to the fact that these infections typically occur in individuals who are incapable of mounting effective immune responses. Patients with neutropenia are extremely susceptible to opportunistic fungal infections. Neutrophils presumably liberate fungicidal substances, such as reactive oxygen species and lysosomal enzymes, and phagocytose fungi for intracellular killing. Cell-mediated immunity is the major mechanism of adaptive immunity against intracellular fungal infections. Histoplasma capsulatum, a facultative intracellular parasite that lives in macrophages, is eliminated by the same cellular mechanisms that are effective against intracellular bacteria. Pneumocystis jiroveci is another intracellular fungus that causes serious infections in individuals with defective cell-mediated immunity. The Th17 cells stimulate inflammation, and the recruited neutrophils and monocytes destroy the fungi. Individuals with defective Th17 responses are susceptible to chronic mucocutaneous Candida infections (see Chapter 21). Th1 responses are protective in intracellular fungal infections, such as histoplasmosis, but these responses may elicit granulomatous inflammation, which is an important cause of host tissue injury in these infections. Viruses typically infect various cell types by receptor-mediated endocytosis after binding to normal cell surface molecules. Viral replication interferes with normal cellular protein synthesis and function and leads to injury and ultimately death of the infected cell. This result is one type of cytopathic effect of viruses, and the infection is said to be lytic because the infected cell is lysed. Innate and adaptive immune responses to viruses are aimed at blocking infection and eliminating infected cells. B, Mechanisms by which innate and adaptive immunity prevent and eradicate virus infections. The mechanisms by which these cytokines block viral replication were discussed in Chapter 4. The most effective antibodies are high-affinity antibodies produced in T-dependent germinal center reactions (see Chapter 12). Antibodies are effective against viruses only during the extracellular stage of the lives of these microbes. Viruses will be extracellular before they infect host cells, or when they are released from infected cells by virus budding or if the infected cells die. Antiviral antibodies bind to viral envelope or capsid antigens and function mainly as neutralizing antibodies to prevent virus attachment and entry into host cells. Secreted antibodies, especially of the IgA isotype, are important for neutralizing viruses within the respiratory and intestinal tracts. In addition to neutralization, antibodies may opsonize viral particles and promote their clearance by phagocytes. Complement activation may also participate in antibody-mediated viral immunity, mainly by promoting phagocytosis and possibly by direct lysis of viruses with lipid envelopes. The importance of humoral immunity in defense against viral infections is supported by the observation that resistance to a particular virus, induced by either infection or vaccination, is often specific for the serologic (antibody-defined) type of the virus. An example is influenza virus, in which exposure to one serologic type does not confer resistance to other serotypes of the virus. Neutralizing antibodies block viral infection of cells and spread of viruses from cell to cell, but after the viruses enter cells and begin to replicate intracellularly, they are inaccessible to antibodies. Therefore, humoral immunity induced by previous infection or vaccination is able to protect individuals from viral infection but cannot by itself eradicate established infection. Susceptibility to such infections is increased in patients and animals deficient in T lymphocytes. As a result, the virus persists in infected cells, sometimes for the life of the individual. Reactivation of the infection is associated with expression of viral genes that are responsible for cytopathic effects and for spread of the virus. These cytopathic effects may include lysis of infected cells or uncontrolled proliferation of the cells. Any deficiency in the host immune response can result in failure to control reactivated latent infection. Some degree of immunopathology accompanies host responses to many, perhaps most, virus infections. This observation appears to contradict the usual situation, in which immunodeficient individuals are more susceptible to infectious diseases than normal individuals are.

Up to onethird of the marrow output of platelets may be trapped at any one time in the normal spleen but this rises to 90% in cases of massive splenomegaly erectile dysfunction treatment japan order genuine sildalist on-line. The glycoproteins of the surface coat are particularly important in the platelet reactions of adhesion and aggregation impotence vitamins buy sildalist 120 mg on line, which are the initial events leading to platelet plug formation during haemostasis psychological erectile dysfunction wiki order sildalist online from canada. The plasma membrane invaginates into the platelet interior to form an open membrane (canalicular) system which provides a large reactive surface to which the plasma coagulation proteins may be selectively absorbed impotence hernia purchase sildalist american express. Platelets are also rich in signalling and cytoskeletal proteins erectile dysfunction doctor in bangalore generic 120mg sildalist with visa, which support the rapid switch from quiescence to activation that follows vessel damage erectile dysfunction 47 years old discount sildalist line. During the release reaction described below, the contents of the granules are discharged into the open canalicular system. Platelet function the main function of platelets is the formation of mechanical plugs during the haemostatic response to vascular injury. In the absence of platelets, spontaneous leakage of blood through small vessels may occur. There are three major platelet functions: adhesion, aggregation and release reactions and amplification. Platelet release reaction and amplification Primary activation by various agonists induces intracellular signalling, leading to the release of granule contents. It is a potent inhibitor of platelet aggregation and prevents their deposition on normal vascular endothelium. Platelet procoagulant activity After platelet aggregation and release, the exposed membrane phospholipid (platelet factor 3) is available for two reactions in the coagulation cascade. The phospholipid surface forms an ideal template for the crucial concentration and orientation of these proteins. This leads to further binding to von Willebrand factor and so results in further platelet adhesion to the subendothelium. Blood coagulation the coagulation cascade Blood coagulation in vivo involves a biological amplification system in which relatively few initiation substances sequentially activate by proteolysis a cascade of circulating precursor proteins (the coagulation factor enzymes) which culminates in the generation of thrombin; this, in turn, converts soluble plasma fibrinogen into fibrin. Fibrin enmeshes the platelet aggregates at the sites of vascular injury and converts the unstable primary platelet plugs to firm, definitive and stable haemostatic plugs. The operation of this enzyme cascade requires local concentration of circulating coagulation factors at the site of injury. Surfacemediated reactions occur on exposed collagen, platelet phospholipid and tissue factor. With the exception of fibrinogen, which is the fibrin clot subunit, the coagulation factors are either enzyme precursors or cofactors (Table 24. Coagulation in vivo the generation of thrombin in vivo is a complex network of amplification and negative feedback loops to ensure a localized and limited production. The generation of thrombin is Chapter 24: Platelets, blood coagulation and haemostasis / 271 Table 24. The generation of thrombin following vascular injury occurs in two waves of very different magnitude. During the initial phase small amounts of thrombin are generated (picomolar concentrations). It is expressed on fibroblasts and small muscles of the vessel wall and in the blood stream on microparticles, and on other nonvascular cells. The factor Xa, in the absence of its cofactor, forms small amounts of thrombin from prothrombin. Importantly, the small amounts of thrombin generated serve to greatly amplify coagulation. Thrombin hydrolyses fibrinogen, releasing fibrinopeptides A and B to form fibrin monomers. Fibrin monomers link spontaneously by hydrogen bonds to form a loose insoluble fibrin polymer. After cleavage by thrombin of small fibrinopeptides A and B from the and chains, fibrin monomer consists of three paired, and chains which rapidly polymerise. This cell provides the basement membrane that normally separates collagen, elastin and fibronectin of the subendothelial connective tissue from the circulating blood. Loss of or damage to the endothelium results in both haemorrhage and activation of the haemostatic mechanism. The reduced blood flow allows contact activation of platelets and coagulation factors. Endothelial cells produce substances that can initiate coagulation, cause vasodilatation, inhibit platelet aggregation or haemostasis, or activate fibrinolysis. This continuing platelet aggregation promotes the growth of the haemostatic plug, which soon covers the exposed connective tissue. The unstable primary haemostatic plug produced by these platelet reactions in the first minute or so following injury is usually sufficient to provide temporary control of bleeding. Stabilization of the platelet plug by fibrin Definitive haemostasis is achieved when fibrin, formed by blood coagulation, is added to the platelet mass and by plateletinduced clot retraction/compaction. Platelet aggregation and release reactions accelerate the coagulation process by providing abundant membrane phospholipid. The fibrin component of the haemostatic plug increases as the fused platelets completely degranulate and autolyse, and after a few hours the entire haemostatic plug is transformed into a solid mass of cross linked fibrin. Physiological limitation of blood coagulation Unchecked, blood coagulation would lead to dangerous occlusion of blood vessels (thrombosis) if the protective mechanisms of coagulation factor inhibitors, blood flow and fibrinolysis were not in operation. Chapter 24: Platelets, blood coagulation and haemostasis / 275 Coagulation factor inhibitors It is important that the effect of thrombin is limited to the site of injury. There is also direct inactivation of thrombin and other serine protease factors by other circulating inhibitors, of which antithrombin is the most potent. The action of protein C is enhanced by another vitamin Kdependent protein, S, which binds protein C to the platelet surface. As with other serine proteases, activated protein C is subject to inactivation by serum protease inactivators (serpins). Blood flow At the periphery of a damaged area of tissue, blood flow rapidly achieves dilution and dispersal of activated factors before fibrin formation has occurred. Activated factors are destroyed by liver parenchymal cells and particulate matter is removed by liver Kupffer cells and other reticuloendothelial cells. Fibrinolysis Fibrinolysis (like coagulation) is a normal haemostatic response to vascular injury. Plasminogen, a proenzyme in blood and tissue fluid, is converted to the serine protease plasmin by activators either from the vessel wall (intrinsic activation) or from the tissues (extrinsic activation). Plasmin generation at the site of injury limits the extent of the evolving thrombus. The split products of fibrinolysis are also competitive inhibitors of thrombin and fibrin polymerization. Protein S is a cofactor that facilitates binding of activated protein C to the platelet surface. Cleavage of peptide bonds in fibrin and fibrinogen produces a variety of split (degradation) products. Large amounts of the smallest fragments can be detected in the plasma of patients with disseminated intravascular coagulation (see p. Circulating plasmin is inactivated by the potent inhibitors 2antiplasmin and 2macroglobulin. A number of simple tests are employed to assess the platelet, vessel wall and coagulation components of haemostasis. Blood count and blood film examination As thrombocytopenia is a common cause of abnormal bleeding, patients with suspected bleeding disorders should initially have a blood count including platelet count and blood film examination. In addition to establishing the presence of thrombocytopenia, the cause may be obvious. Modern counters measure platelet volume but this parameter is not used routinely in clinical practice for diagnosis of platelet disorders. Platelet count and the tests of platelet function are also used in screening patients with a bleeding disorder (p. Tissue thromboplastin (a brain extract) or [synthetic] tissue factor with lipids and calcium is added to citrated plasma. If there is no correction or incomplete correction with normal plasma, the presence of an inhibitor of coagulation is suspected. This usually requires a supply of plasma from patients with hereditary deficiency of the factor in question or artificially produced factordeficient plasma. The corrective effect of the unknown plasma on the prolonged clotting time of the deficient substrate plasma is then compared with the corrective effect of normal plasma. Bleeding time the bleeding time is not a reliable assessment of platelet function as it is insensitive and has poor reproducibility. The test involved the application of pressure to the upper arm with a blood pressure cuff, after which small incisions are made in the flexor surface forearm skin. The bleeding time is prolonged in thrombocytopenia but is normal in vascular causes of abnormal bleeding. Tests of platelet function Conventional platelet aggregometry measures the fall in light absorbance in plateletrich plasma as platelets aggregate. Initial (primary) aggregation is caused by an external agent; the secondary response is caused by aggregating agents released from the platelets themselves. Flow cytometry is now increasingly used in routine practice to identify platelet glycoprotein defects. The analysis may give falsenegative results with relatively common platelet defects. Tests of fibrinolysis Testing for hyperfibrinolysis by traditional tests, such as the euglobulin clot lysis times, is rarely performed. Ddimer is a measurement of fibrin degradation products and is an indication of sequential thrombin and then plasmin activity. The test can be performed on citrated plasma samples along with simple coagulation tests. There are many causes of a high Ddimer, including infection, cancer and pregnancy, as well as venous thromboembolism. Blood coagulation in vivo in response to vascular Normal haemostasis requires vasoconstriction, platelet aggregation and blood coagulation. The intact endothelial cell separates collagen and other subendothelial connective tissues that would stimulate platelet aggregation from circulating blood. The endothelial cells also produce prostacyclin, nitric oxide and an ectonucleotidase, which inhibit platelet aggregation. Platelets are produced from megakaryocytes in the bone marrow stimulated by thrombopoietin. They have surface glycoproteins which facilitate direct adherence to subendothelial tissues and also, via von Willebrand factor, to collagen, to other platelets (aggregation) and to fibrinogen. Platelets contain different types of storage granules which are released after platelet activation. Dissolution of fibrin clots (fibrinolysis) occurs by activation of plasminogen to plasmin. Chapter 25: Bleeding disorders / 279 Abnormal bleeding this may result from: 1 Vascular disorders; 2 Thrombocytopenia; 3 Defective platelet function; or 4 Defective coagulation. Vascular and platelet disorders tend to be associated with bleeding from mucous membranes and into the skin, whereas in coagulation disorders the bleeding is often into joints or soft tissue (Table 25. The first three categories are discussed in this chapter and the disorders of blood coagulation follow in Chapter 26. Frequently, the bleeding is mainly in the skin causing petechiae, ecchymoses or both. The bleeding time is usually normal and the other tests of haemostasis are also normal. Inherited vascular disorders Hereditary haemorrhagic telangiectasia this uncommon disease is transmitted as an autosomal dominant trait. Various genetic defects underlie the disease such as mutations of the endothelial protein, endoglin. There are dilated microvascular swellings which appear during childhood and become more numerous in adult life. Pulmonary, hepatic, splenic and cerebral arteriovenous shunts are seen in a minority of cases and may need local treatment. Recurrent epistaxes are frequent and recurrent gastrointestinal tract haemorrhage may cause chronic iron deficiency anaemia. Treatment is with embolization, laser treatment, oestrogens, tranexamic acid and iron supplementation. Thalidomide, lenalinomide and bevcizumab (antivascular endothelial growth factor) have been use to try to reduce gastrointestinal bleeding in severe cases. Patients may present with superficial bruising and purpura following minor trauma or after the application of a tourniquet. Acquired vascular defects 1 Simple easy bruising is a common benign disorder which occurs in otherwise healthy women, especially those of childbearing age. Vascular bleeding disorders the vascular disorders are a heterogeneous group of conditions characterized by easy bruising and spontaneous bleeding from the small vessels.

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