Pernicious anemia, expressed as megaloblastic anemia, exists in individuals who fail to produce a glycoprotein, Castle's intrinsic factor (CIF). It is commonly thought that the parietal cells of the stomach do not secrete CIF due to autoantibodies, thus not allowing vitamin [B.sub.1,2] (cobalamin) to bond with CIF and so to be absorbed by the distal ileum. The failure of CIF secretion is associated with achlorhydria and gastric mucosa atrophy. This acquired disease becomes symptomatic usually after the age of 50 and is most common in individuals of northern European descent, especially Scandinavians. It is diagnosed with the Schilling test.
Anemia of any cause may result in increased cardiac output, especially when the hemoglobin level drops to 7 g/dl or less. Tachycardia may not be present in chronic anemia, and the increased cardiac output at rest usually reflects an increased cardiac stroke volume.[4,5] The increased cardiac output is achieved at the cost of increased work of the left ventricle. Right atrial, right ventricular, and pulmonary arterial pressures are usually normal unless cardiac decompensation develops.[4,7] Left ventricular end-diastolic pressure remains unchanged.
Increased cardiac output in pernicious anemia and in other severe chronic anemias is of importance in maintaining an adequate oxygen supply to the tissues, and is facilitated by alterations in left ventricular afterload and myocardial contractility. Although ventricular end-diastolic volume, which is the preload of the left side of the heart, seems to be unchanged, myocardial contractility appears to increase.[6,9,10] Afterload and left ventricular wall stress, having as major determinants vascular resistance and blood viscosity, are reduced. Decrease in peripheral vascular resistance in severe pernicious anemia is of great importance in producing increased cardiac output. Moreover, lowered blood viscosity associated with anemia complements the increased cardiac output. Effects of decreased viscosity with low hematocrit vaues can result in a fivefold increase in coronary perfusion.
Maximum myocardial oxygen transport shows an inverted U-shaped relationship with the hematocrit value. At extremely low or extremely high concentrations of red blood cells, myocardial oxygen transport may decrease due to decreased oxygen carrying capacity on the one hand and increased blood viscosity on the other. Thus, the peak of the above curve occurs at or slightly above the normal hematocrit level. Compensatory mechanisms to counteract the low hematocrit level include alternations in peripheral vascular resistance in order to redistribute cardiac output to selective vascular beds, so that during anemia; the increasing blood flow is proportionally greater in the coronary bed than in the renal, mesenteric, or femoral beds. This phenomenon is owed to vasoconstriction or vasodilation because of neurohumoral and/or local autoregulatory factors. Also, in chronic anemia the red blood cells develop increased levels of 2,3-diphosphoglycerate, which facilitates release of oxygen from hemoglobin; however, this mechanism may be of secondary importance in severe anemia since the arteriovenous difference is decreased 3 volumes per 100 ml of blood, compared with 4 to 5 volumes per 100 ml of blood in normal subjects. Another important mechanism of increased oxygen delivery to the heart in pernicious anemia may be increased utilization of coronary collateral vessels. Release of local vasodilators may help improve collateral blood flow after development of severe anemia.
If these adaptation mechanisms in severe anemia do not compensate adequately, angina pectoris may develop in these patients in spite of normal coronary arteries. Angina pectoris caused by severe anemia usually develops at very low hemoglobin levels, in the range of 3 to 4 g/dl. Coombs noted an association between severe pernicious anemia and anginalike pain, especially on exertion. The true incidence of angina pectoris associated with pernicious anemia could not be determined accurately, since many of the patients reported did not have adequate studies of the coronary circulation to rule out associated coronary artery disease. Clinically, the incidence appears to be in the range of 2 to 3 percent. Although severe anemia is not a common cause of angina, it should always be listed in the differential diagnosis of angina pectoris.
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 Pedersen AB, Mosbech J. Morbidity of pernicious anemia. Acta Med Scand 1969; 185:449-52
 Brannon ES, Merrill AJ, Warren JV, Stead EA Jr. The cardiac output in patients with chronic anemia as measured by the technique of right atrial catheterization. J Clin Invest 1945; 24:332-36
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 Baer WR, Vlahakes JG, Uhlig NP, Hoffman IEJ. Maximum myocardial oxygen transport during anemia and polycythemia in dogs. Am J Physiol 1987; 252(Heart Circ Physiol 21):H1086-95
 Fay FC, Chen ZYR, Schuessler GB, Chien S. Effects of hematocrit variations on regional hemodynamics and oxygen transport in the dog. Am J Physiol 1980; 238(Heart Circ Physiol 7):H545-52
 Benesch R, Benesch RE. The effect of organic phosphates from the human erythrocyte on the allosteric properties of hemoglobin. Biochem Biophys Res Commun 1967; 26:162
 Scheel KW, Williams SE. Hypertrophy and coronary and collateral vascularity in dogs with severe chronic anemia. Am J Physiol 1985; 249(Heart Circ Physiol 18):H1031-37
 Coombs CF. A note on the cardiac symptoms of pernicious anemia, with particular reference to cardiac pain. BMJ 1926; 2:185
 Willius FA, Giffin HZ. The anginal syndrome in pernicious anemia. Am J Med Sci 1927; 174:30-3
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