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INTRODUCTION

Exposure to hematotoxins may affect blood cell survival (denaturation of hemoglobin and hemolysis), porphyrin synthesis and metabolism (including some porphyrias), blood cell formation (aplasia), risk for hematopoietic neoplasms, or coagulation (through development of thrombocytopenia).

DISORDERS ASSOCIATED WITH SHORTENED RED BLOOD CELL SURVIVAL

METHEMOGLOBINEMIA & HEMOLYSIS PRODUCED BY OXIDANT CHEMICALS

Methemoglobin is formed by the oxidation of ferrous (Fe2+) hemoglobin to ferric (Fe3+) hemoglobin. It was first recognized in the 1800s, when coal tars were converted into individual chemicals that served as precursors for many products ranging from explosives to synthetic dyes and perfumes. Overexposure to these chemicals—which included anilines, nitrobenzenes, and quinones—was common, and little was known about their potential toxicity. Workers in these plants came to be known as “blue workers” because they suffered from “blue lip” as a result of the chronic cyanosis from toxin-induced methemoglobinemia that developed in many of them. Gradually it was recognized that oxidation of hemoglobin was toxic to red blood cells and could be followed by an acute and life-threatening hemolysis known as Heinz body anemia. Heinz bodies are red blood cell inclusions that represent precipitated hemoglobin and are seen classically in individuals with a deficiency of glucose-6-phosphate dehydrogenase (G6PD) after exposure to an oxidant stress. Normal individuals exposed to large amounts of oxidant chemicals will develop methemoglobinemia and, occasionally, Heinz body hemolytic anemia.

Pathophysiology of Methemoglobinemia & Oxidant Hemolysis

Hemoglobin is unique in its ability to combine reversibly with oxygen without oxidizing its iron moiety. The small amount of oxidized hemoglobin or methemoglobin produced is readily reduced by an efficient enzyme system linked to energy provided by glucose metabolism via the Embden-Meyerhof pathway (Figure 24–1).

Figure 24–1.

Oxidation of hemoglobin by the Embden-Meyerhof pathway.

Methemoglobin is dangerous because of its inability to bind oxygen and because it increases the oxygen affinity of the remaining heme groups in hemoglobin tetramer, thereby decreasing oxygen delivery to the tissues. Oxidation results in denaturation of hemoglobin with the formation of precipitated hemoglobin (Heinz bodies) within the red cell. The presence of Heinz bodies alters the surface membrane of the red cell, causing increased rigidity and leakage. Macrophages in the reticuloendothelial system of the spleen and liver (the extravascular compartment) sense the altered red cell surface and remove Heinz bodies via partial phagocytosis (extravascular hemolysis). Because the red cell surface is unable to reseal and form a spherocyte (as in autoimmune hemolysis), the red cell remains intact as a cell with a piece missing, the so-called bite, or blister, cell. Heinz bodies also may be formed from a second form of denatured hemoglobin, sulfhemoglobin. Unlike methemoglobin, sulfhemoglobin is irreversibly associated with the heme moiety.

The development of methemoglobinemia or oxidative hemolysis in ...

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