EDITORIAL: Why do young women (donors) faint?

I n humans, tolerance to orthostasis requires the successful integration of multiple elements of cardiovascular control. Syncope or near-syncope may occur when there is an abnormally large postural decrease in central blood volume, cardiac filling pressure, stroke volume, and cardiac output or inadequate (or inappropriate) neurohumoral reflex responses to orthostasis, primarily tachycardia and vasoconstriction. Young women are more susceptible to orthostatic intolerance compared to similarly aged men; this sex difference is especially dramatic under hypovolemic conditions when circulating blood volume is reduced. For example, postflight syncope or near-syncope is greatest in women astronauts, and orthostatic tolerance decreases are greater in women than men after a period of headdown bed rest (i.e., simulated microgravity exposure) or after acute dehydration. Additionally, postural orthostatic tachycardia syndrome (also called chronic orthostatic intolerance, in which patients are unable to stand or remain upright for prolonged periods of time due to intolerable light-headedness, weakness, and near-syncope) affects primarily young women, with perturbed blood volume regulation and reduced plasma volume in many of these patients. Circulating blood volume has a profound effect on arterial pressure during orthostasis in humans. Individuals with reduced vascular volumes exhibit subnormal cardiac filling pressure and the capacity to buffer orthostatic reductions in central blood volume is limited. In this issue of TRANSFUSION, Kamel and coworkers provide strong evidence of orthostatic intolerance in young women after blood donation. In this large retrospective study, the authors assessed 793,293 donors from 15 blood centers and identified risk factors for moderate or severe adverse reactions to blood donation. For the sake of clarity, we will use the term “neurally mediated” rather than “vasovagal” to describe these reactions because the relative contribution of sympathetic withdrawal (leading to vasodilation) and increased vagal tone (leading to bradycardia and reduced cardiac output) may be quite variable among individuals who faint. They found that low estimated blood volume, youth, and first-time donor status are major risk factors for both immediate and delayed reactions, while female sex is a better predictor of a delayed neurally mediated reaction. What are the clinical implications of these findings? As the authors state, the identified characteristics may shape policy and procedures intended to reduce the risks of adverse reactions to blood donation; understanding the physiologic basis of delayed reactions may lead to the development of appropriate interventions to reduce their likelihood. The observations made by Kamel and coworkers are novel. However, the mechanisms underlying sex differences in orthostatic tolerance are not completely understood. It is possible that certain sex-specific factors such as differences in some hormonal levels, which may affect the neurohumoral regulation of arterial pressure, or physical characteristics such as a smaller and less distensible heart, may affect orthostatic blood pressure control. Sex differences in arterial pressure have been suggested to be associated with the sex hormones. Among these, estrogen is proposed to be responsible for the lower blood pressure in premenopausal women. Meyer and colleagues showed previously that estrogen replacement attenuated resistance artery adrenergic sensitivity via endothelial vasodilators such as nitric oxide and prostaglandins in female rats. It was also found that estrogen supplementation selectively attenuated vasoconstrictor responses in perimenopausal women. Conversely, recent data from healthy young women demonstrated that the fluctuations of female sex hormones estrogen and progesterone during the normal menstrual cycle did not alter arterial pressure and peripheral vasoconstriction in the upright posture, suggesting that the relationship between blood pressure and endogenous levels of sex hormones is complex and is probably affected by other factors. Sympathetic neural control plays an important role in arterial pressure maintenance through peripheral vasoconstriction during orthostasis in humans. When this compensatory mechanism fails or is overwhelmed, blood pressure will drop and syncope may occur. Sex differences in orthostatic tolerance have been suggested to be related to sympathetic neural control. One previous study with the microneurographic technique to directly measure intraneural efferent sympathetic nerve discharges demonstrated that healthy young men and women had comparable sympathetic neural responses during acute upright posture in normovolemic and hypovolemic conditions; in addition, vasoconstrictor responses to tilting were similar between sexes under both conditions. Recently, it was found that healthy young men and women had comparable sympathetic neural and vasoconstrictor responses during prolonged (i.e., 45 min) orthostasis. These results do not support the notion that TRANSFUSION 2010;50:522-525.