Chapter 34: Clinical Manifestations and Classification of Erythrocyte Disorders

SUMMARY

Anemias are characterized by a decrease and polycythemias by an increase of the red cell mass. In most clinical situations, changes in red cell mass are inferred from the hemoglobin concentration or hematocrit. Some red cell disorders are associated with compensated hemolysis without or with only slight anemia. Their clinical manifestations are evident not by the effects of anemia but by changes associated with catabolism of hemoglobin such as an increase in serum bilirubin and, if sustained, cholelithiasis, decreased haptoglobin, and usually chronic reticulocytosis. Some red cells disorders are only showcased by morphologic abnormalities as exemplified by hereditary elliptocytosis unaccompanied by hemolysis or anemia.

 The anemias have their principal effect by decreasing the oxygen-carrying capacity of blood and their severity is best considered in terms of blood hemoglobin concentration. Anemia may cause symptoms because of tissue hypoxia (e.g., fatigue, dyspnea on exertion). Some manifestations are also caused by compensatory attempts to ameliorate hypoxia (e.g., hyperventilation, tachycardia, and increased cardiac output). These manifestations are a function of the severity and rapidity of onset of the anemia. Tissue hypoxia sensing is ubiquitous and is signaled by an increased level of hypoxia-inducible transcription factors (HIFs)-1 and -2. HIFs upregulate transcription of many genes, in addition to the principal erythropoietic factor erythropoietin (EPO), that are involved in erythropoiesis, but also in angiogenesis, energy metabolism, and iron balance. The classification of anemia should take into account new kinetic and molecular findings.

 The polycythemias (erythrocytoses) are best expressed in terms of the packed red cell volume (hematocrit), as their clinical manifestations are primarily related to the expanded red cell mass and resulting increased viscosity of blood, and other specific features related to the pathophysiology stemming from a molecular causative defect (e.g., thrombosis in polycythemia vera, cyanosis in congenital methemoglobinemia). The polycythemias may be primary, caused by somatic or germline mutation(s) dysregulating expansion of erythroid progenitors and, thus, red cell production, e.g., clonal expansion of a multipotential hematopoietic cell (polycythemia vera) or gain-of-function mutations of the EPO receptor (EPOR) on red cell progenitors—or secondary, caused by increased levels of circulating erythropoiesis-stimulating factors, usually EPO, as a result of tissue hypoxia (e.g., chronic pulmonary disease, high oxygen-affinity hemoglobin mutants, cobalt poisoning). Some polycythemias have hypersensitive erythroid progenitors, as well as increased levels of EPO, and thus share features of both primary and secondary polycythemia; these include Chuvash polycythemia and some other congenital disorders of hypoxia sensing. Persons with relative (spurious) polycythemia have an increased hematocrit as a result of a decreased plasma volume but a normal red cell mass.

Acronyms and Abbreviations:

EGLN1, a gene encoding PHD2 protein; EPAS1, a gene encoding hypoxia-inducible factor-2α; EPO, erythropoietin; EPOR, erythropoietin receptor; HIF, hypoxia-inducible factor; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PFCP, primary familial and congenital polycythemia; PHD2, prolyl hydroxylase domain-containing protein 2; VHL, a gene encoding von Hippel-Lindau tumor suppressor.