Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 13)

Pyrimidine 5-Nucleotidase (P5N) Deficiency P5N is a key enzyme in the catabolism of nucleotides arising from the degradation of nucleic acids that takes place in the final stages of red cell maturation. How exactly its deficiency causes HA is not well understood, but a highly distinctive feature of this condition is a morphologic abnormality of the red cells known as basophilic stippling. The condition is rare, but it probably ranks third in frequency among red cell enzyme defects (after G6PD deficiency and PK deficiency). The anemia is lifelong, of variable severity, and may benefit from splenectomy.Familial Hemolytic Uremic Syndrome...
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Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 13) Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 13) Pyrimidine 5-Nucleotidase (P5N) Deficiency P5N is a key enzyme in the catabolism of nucleotides arising from thedegradation of nucleic acids that takes place in the final stages of red cellmaturation. How exactly its deficiency causes HA is not well understood, but ahighly distinctive feature of this condition is a morphologic abnormality of the redcells known as basophilic stippling. The condition is rare, but it probably ranksthird in frequency among red cell enzyme defects (after G6PD deficiency and PKdeficiency). The anemia is lifelong, of variable severity, and may benefit fromsplenectomy. Familial Hemolytic Uremic Syndrome (HUS) This disorder is unique because, now that its basis has been elucidated, wecan clearly see that hemolysis is due to an inherited defect, but this is external tored cells. HUS is defined as a microangiopathic hemolytic anemia with fragmentederythrocytes in the peripheral blood smear, thrombocytopenia (usually mild), andacute renal failure. An infection is usually the trigger of the syndrome, which tendsto recur. When it does, the prognosis is serious. Although familial HUS is rare,studies of affected members from more than 100 families have revealed numerousmutations in any of three complement regulatory proteins: membrane cofactorprotein, factor H, and factor I. It is thought that when complement is activatedthrough the alternative pathway following damage to endothelial cells in thekidney, one of the results will be brisk hemolysis. Thus, the much more commonShiga toxin–related HUS can be regarded as a phenocopy of familial HUS. Acquired Hemolytic Anemia Mechanical Destruction of Red Cells Although red cells are characterized by the remarkable deformability thatenables them to squeeze through capillaries narrower than themselves thousandsof times in their lifetime, there are at least two situations in which they succumb toshear, if not to wear and tear; the result is intravascular hemolysis resulting inhemoglobinuria. One situation, march hemoglobinuria, is acute and self-inflicted.Why a marathon runner may sometimes develop this complication and at anothertime does not is unclear (perhaps the footwear needs attention). A similarsyndrome may develop after prolonged barefoot ritual dancing or vigorous bongodrumming. The other situation, which has been called microangiopathic hemolyticanemia, (Table 101-6) is chronic and iatrogenic; it takes place in patients withprosthetic heart valves, especially when paraprosthetic regurgitation is present. Ifthe hemolysis consequent to mechanical trauma to the red cells is mild, andprovided the supply of iron is adequate, it may be largely compensated. If morethan mild anemia develops, reintervention to correct regurgitation may berequired. Toxic Agents and Drugs A number of chemicals with oxidative potential, whether medicinal or not,can cause hemolysis even in people who are not G6PD-deficient (see above).Examples are hyperbaric oxygen (or 100% oxygen), nitrates, chlorates, methyleneblue, dapsone, cisplatin, and numerous aromatic (cyclic) compounds. Otherchemicals may be hemolytic through nonoxidative, largely unknown mechanisms;examples are arsine, stibine, copper, and lead. The HA caused by lead poisoning ischaracterized by basophilic stippling: it is in fact a phenocopy of that seen in P5Ndeficiency (see above), suggesting it is mediated at least in part by lead inhibitingthis enzyme. In these cases hemolysis appears to be mediated by a direct chemical actionon red cells. But drugs can cause hemolysis through at least two othermechanisms. (1) A drug can behave as a hapten and induce antibody production.In rare subjects this happens, for instance, with penicillin. Upon a subsequentexposure, red cells are caught as innocent bystanders in the reaction betweenpenicillin and antipenicillin antibodies. Hemolysis will subside as soon aspenicillin administration is stopped. (2) A drug can trigger, perhaps throughmimicry, the production of an antibody against a red cell antigen. The best-knownexample is methyldopa, an antihypertensive agent no longer in use, which in asmall fraction of patients stimulated the production of the Rhesus antibody anti-e.In patients who have this antigen, the anti-e is a true autoantibody, which wouldthen cause an autoimmune HA (see below). Usually HA would gradually subsideonce methyldopa was discontinued. Nucleosides may also cause hemolysis by depletion of ATP. Ribavirin, adrug used in the treatment of hepatitis C, causes the destruction of red cellsth ...