Harrison's Internal Medicine Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss
Definitions A finite life span is a distinct characteristic of red cells. Hence, a logical, time-honored classification of anemias comprises three groups: decreased production of red cells, increased destruction of red cells, and acute blood loss. Red cell destruction and acute loss, both associated with increased reticulocyte production, are covered in this chapter. Red cell production defects are discussed in Chaps. 98, 99, and 100.
Hemolytic Anemias Due to Abnormalities of the MembraneCytoskeleton Complex
The detailed architecture of the red cell membrane is complex, but its basic design is relatively simple (Fig. 101-2). The lipid bilayer, which incorporates phospholipids and cholesterol, is spanned by a number of proteins that have their hydrophobic transmembrane domains embedded in the membrane. Most of these proteins have hydrophilic domains extending toward both the outside and the inside of the cell.
Autoimmune Hemolytic Anemia (AIHA) Except for countries where malaria is endemic, AIHA is the most common form of acquired hemolytic anemia. In fact, not quite appropriately, the two phrases are sometimes used synonymously.
Pathophysiology AIHA is caused by an autoantibody directed against a red cell antigen, i.e., a molecule present on the surface of red cells. The autoantibody binds to the red cells. Once a red cell is coated by antibody, it will be destroyed by one or more mechanisms.
Anemia Due to Acute Blood Loss Blood loss causes anemia by two main mechanisms: first, by the direct loss of red cells; second, because if the loss of blood is protracted, it will gradually deplete the iron stores, eventually resulting in iron deficiency. Iron-deficiency anemia is discussed in Chap. 98.
Here we are concerned with post-hemorrhagic anemia, which follows acute blood loss. This can be external (as after trauma or due to postpartum hemorrhage) or internal (e.g., from bleeding in the gastrointestinal tract, rupture of the spleen, rupture of an ectopic pregnancy).
Table 101-2 General Features of Hemolytic Disorders
Spleen may be enlarged; bossing of skull in severe congenital cases
From normal to severely reduced
Increased (mostly unconjugated)
Reduced to absent
Note: MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; LDH, lactate dehydrogenase.
Abnormalities of the Glycolytic Pathway (Fig. 101-1) Since red cells, in the course of their differentiation, have sacrificed not only their nucleus and their ribosomes but also their mitochondria, they rely exclusively on the anaerobic portion of the glycolytic pathway for producing energy in the form of ATP. Most of the ATP is required by the red cell for cation transport against a concentration gradient across the membrane. If this fails, due to a defect of any of the enzymes of the glycolytic pathway, the result will be hemolytic disease.
Clinical Presentation and Diagnosis The spectrum of clinical severity of HS is broad. Severe cases may present in infancy with severe anemia, whereas mild cases may present in young adults or even later in life. In women, HS is sometimes first diagnosed when anemia is investigated during pregnancy. The main clinical findings are jaundice, an enlarged spleen, and often gallstones; frequently it is the finding of gallstones in a young person that triggers diagnostic investigations.
Peripheral blood smear from a 5-year-old G6PD-deficient boy with acute favism.
A very small minority of subjects with G6PD deficiency have CNSHA of variable severity. The patient is always a male, usually with a history of NNJ, who may present with anemia or unexplained jaundice, or because of gallstones later in life. The spleen may be enlarged. The severity of anemia ranges from borderline to transfusion-dependent. The anemia is usually normo-macrocytic, with
reticulocytosis. Bilirubin and LDH are increased.
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).
Bone Marrow Failure—Relationship between PNH and AA It is not unusual that patients with firmly established PNH have a previous history of well-documented AA. On the other hand, sometimes a patient with PNH becomes less hemolytic and more pancytopenic and ultimately has the clinical picture of AA. Since AA is probably an organ-specific autoimmune disease in which T cells cause damage to hematopoietic stem cells, the same may be true of PNH, with the specific proviso that the damage spares PNH stem cells. Skewing of the T cell repertoire in patients with PNH supports this notion.
Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành y học dành cho các bạn tham khảo đề tài: Hemolytic anemia due to acute cytomegalovirus infection in an immunocompetent adult: a case report and review of the literature
RBC metabolism. The Embden-Meyerhof pathway (glycolysis) generates ATP for energy and membrane maintenance. The generation of NADPH maintains hemoglobin in a reduced state. The hexose monophosphate shunt generates NADPH that is used to reduce glutathione, which protects the red cell
against oxidant stress. Regulation of 2,3-bisphosphoglycerate levels is a critical determinant of oxygen affinity of hemoglobin.
Peripheral blood smear from patients with membrane-cytoskeleton abnormalities. A. Hereditary spherocytosis. B. Hereditary elliptocytosis, heterozygote. C. Elliptocytosis, with both alleles of the α-spectrin gene mutated. [From L Luzzatto, in J Gribben and D Pravan (eds): Molecular Hematology, 2d edition. Oxford, Blackwell, 2005; with permission.]
Table 101-3 Inherited Diseases of the Red Cell MembraneCytoskeleton
Chromoso mal Location
Protei n Produced s)
Disease( with s
Pyruvate Kinase Deficiency: Treatment Management of PK deficiency is mainly supportive. In view of the marked increase in red cell turnover, oral folic acid supplements should be given constantly. Blood transfusion should be used as necessary, and iron chelation may have to be added if the blood transfusion requirement is high enough to cause iron overload. In these patients, who have more severe disease, splenectomy may be beneficial.
Epidemiology G6PD deficiency is widely distributed in tropical and subtropical parts of the world (Africa, Southern Europe, the Middle East, Southeast Asia, and Oceania) (Fig. 101-5) and wherever people from those areas have migrated; a conservative estimate is that at least 400 million people have a G6PD-deficiency gene. In several of these areas, the frequency of a G6PD-deficiency gene may be as high as 20% or more.
Severe acute AIHA can be a medical emergency. The immediate treatment almost invariably includes transfusion of red cells. This may pose a special problem because if the antibody involved is "unspecific," all the blood units crossmatched will be incompatible. In these cases it is often correct, paradoxically, to transfuse incompatible blood, the rationale being that the transfused red cells will be destroyed no less but no more than the patient's own red cells, and in the meantime the patient stays alive.
PNH has about the same frequency in men and women, and it is encountered in all populations throughout the world, but it is a rare disease: its prevalence is 1–5 per million (it may be somewhat less rare in Southeast Asia and in the Far East). There is no evidence of inherited susceptibility. PNH has never been reported as a congenital disease, but it can present in small children or in people in their seventies, although most patients are young adults.
The patient may seek medical attention because one morning she or he has passed "blood instead of urine."...
Definition and Differential Diagnosis PRCA is characterized by anemia, reticulocytopenia, and absent or rare erythroid precursor cells in the bone marrow. The classification of PRCA is shown in Table 102-4. In adults, PRCA is acquired. An identical syndrome can occur constitutionally: Diamond-Blackfan anemia, or congenital PRCA, is diagnosed at birth or in early childhood and often responds to glucocorticoid treatment; a minority of patients have etiologic mutations in a ribosomal RNA processing gene called RPS19.
Ineffective Hemopoiesis There is an accumulation of unconjugated bilirubin in plasma due to the death of nucleated red cells in the marrow (ineffective erythropoiesis). Other evidence for this includes raised urine urobilinogen, reduced haptoglobins and positive urine hemosiderin, and a raised serum lactate dehydrogenase. A weakly positive direct antiglobulin test due to complement can lead to a false diagnosis of autoimmune hemolytic anemia.
Causes of Cobalamin Deficiency
Cobalamin deficiency is usually due to malabsorption. The only other cause is inadequate dietary intake.