Page 854 - Williams Hematology ( PDFDrive )

828 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 829

I and H) in plasma and C3b receptors on the RBC surface to alter the Complement fixation by cold agglutinins may affect RBC injury by
hemolytic function of cell-bound C3b and C4b. Glycosylphosphat- two major mechanisms: (1) direct lysis and (2) opsonization for hepatic
187
idylinositol-linked erythrocyte membrane proteins, such as decay- and splenic macrophages. Both mechanisms probably operate to vary-
accelerating factor (DAF; CD55) and homologous restriction factor ing degrees in any patient. Direct lysis requires propagation of the full
(HRF; CD59), may limit the action of autologous complement on auto- C1 to C9 sequence on the RBC membrane. If this process occurs to a
antibody-coated RBCs. 188–190 DAF inhibits the formation and function significant degree, the patient may experience intravascular hemolysis
188
of cell-bound C3-converting enzyme, thus, indirectly limiting forma- leading to hemoglobinemia and hemoglobinuria. Intravascular hemoly-
tion of C5-converting enzyme. HRF, on the other hand, impedes C9 sis of this severity is relatively rare because phosphatidylinositol-linked
binding and formation of the C5b–9 membrane attack complex. 189 RBC membrane proteins (DAF and HRF) protect against injury by
Cytotoxic activities of macrophages and lymphocytes also may play autologous complement components. Thus, the complement sequence
a role in the destruction of RBCs in warm-antibody AHA. Monocytes on many RBCs is completed only through the early steps, leaving
can lyse IgG-coated RBCs in vitro independently of phagocytosis. 191,192 opsonic fragments of C3 (C3b/C3bi) and C4 (C4b) on the cell surface.
Cell-bound complement is neither necessary nor sufficient for such The fragments provide only a weak stimulus for phagocytosis by mono-
192
cytotoxicity, but bound C3b/C3d can potentiate the effects of IgG. In cytes in vitro. 184,203 However, activated macrophages may ingest C3b-
one study, cytotoxicity, but not phagocytosis, was inhibited by hydro- coated particles avidly. Accordingly, RBCs heavily coated with C3b
204
cortisone in vitro. Lymphocytes also can lyse IgG antibody-coated (and/or C3bi) may be removed from the circulation by macrophages
191
RBCs in vitro. 193–195 The relative contribution of antibody-dependent either in the liver or, to a lesser extent, the spleen. 171,197,205,206 The trapped
monocyte- and lymphocyte-mediated cytotoxicity to RBC destruction RBCs may be ingested entirely or released back into the circulation as
in patients with warm-antibody AHA is not known. spherocytes after losing plasma membrane.
51
In vivo studies of the fate of Cr-labeled C3b-coated RBCs 170,197,205,206
Pathogenic Effects of Cold Agglutinins and Hemolysins indicate many of the erythrocytes trapped in the liver or spleen gradually
Most cold agglutinins are unable to agglutinate RBCs at temperatures may reenter the circulation. The released cells generally are coated with
higher than 30°C. The highest temperature at which these antibodies the opsonically inactive C3 fragment C3dg. Conversion of cell-bound
cause detectable agglutination is termed the thermal amplitude. The C3b or C3bi to C3dg results from the action of the naturally occurring
value varies considerably among patients. Generally, patients with cold complement inhibitor factor I in concert with factor H or CR1 recep-
agglutinins with higher thermal amplitudes have a greater risk for cold tors. The surviving C3dg-coated RBCs circulate with a near-normal
181
agglutinin disease. For example, active hemolytic anemia has been life span 170,197,205,206 and are resistant to further uptake of cold agglutinins
9
observed in patients with cold agglutinins of modest titer (e.g., 1:256) or complement. 197,205,207 However, C3dg-coated RBCs also may react in
and high thermal amplitudes. 196 vitro with anticomplement (anti-C3) serum in the DAT. In fact, most of
The pathogenicity of a cold agglutinin depends upon its ability to the antiglobulin-positive RBCs of patients with cold agglutinin disease
bind host RBCs and to activate complement. 10,182,197,198 This process is are coated with C3dg.
called complement fixation. Although in vitro agglutination of the RBCs In paroxysmal cold hemoglobinuria, the mechanism of hemolysis
may be maximal at 0 to 5°C, complement fixation by these antibodies probably parallels in vitro events (see “Serologic Features” below). Dur-
may occur optimally at 20 to 25°C and may be significant at even higher ing severe chilling, blood flowing through skin capillaries is exposed to
physiologic temperatures. 10,196,197 Agglutination is not required for the low temperatures. The Donath-Landsteiner antibody and early acting
process. The great preponderance of cold agglutinin molecules are IgM complement components presumably bind to RBCs at the lowered tem-
pentamers, but small numbers of IgM hexamers with cold agglutinin peratures. Upon return of the cells to 37°C in the central circulation,
activity are found in patients with cold agglutinin disease. Hexamers the cells are lysed by propagation of the terminal complement sequence
fix complement and lyse RBCs more efficiently than do pentamers, sug- through C9. The Donath-Landsteiner antibody itself dissociates from
gesting that hexameric IgM plays a role in the pathogenesis of hemolysis the RBCs at 37°C. Erythrocyte membrane proteins that restrict C5b–9
in these patients. 199 assembly (e.g., HRFs) may be less effective in controlling Donath-
Cold agglutinins may bind to RBCs in superficial vessels of the Landsteiner antibody-initiated complement activation than that initi-
extremities, where the temperature generally ranges between 28 and ated by cold agglutinins.
200
31°C, depending upon ambient temperature. Cold agglutinins of high
thermal amplitude may cause RBCs to aggregate at this temperature, Pathogenesis of Drug-Mediated Immune Injury
thereby impeding RBC flow and producing acrocyanosis. In addition, Table 54–3 summarizes the three mechanisms of drug-mediated
the RBC-bound cold agglutinin may activate complement via the classic immune injury to RBCs. Drugs also may mediate protein adsorption
pathway. Once activated complement proteins are deposited onto the to RBCs by nonimmune mechanisms, but RBC injury does not occur.
RBC surface, the cold agglutinin need not remain bound to the RBCs Hapten or Drug Adsorption Mechanism This mechanism applies
for hemolysis to occur. Instead, the cold agglutinin may dissociate from to drugs that can bind firmly to proteins, including RBC membrane pro-
the RBCs at the higher temperatures in the body core and again be capa- teins. The classic setting is very-high-dose penicillin therapy, 28–34 which
ble of binding other RBCs at the lower temperatures in the superficial is encountered less commonly today than in previous decades.
vessels. As a result, patients with cold agglutinins of high thermal ampli- Most individuals who receive penicillin develop IgM antibodies
201
tude tend toward a sustained hemolytic process and acrocyanosis. directed against the benzylpenicilloyl determinant of penicillin, but this
In contrast, patients with antibodies of lower thermal amplitude require antibody plays no role in penicillin-related immune injury to RBCs. The
significant chilling to initiate complement-mediated injury of RBCs. antibody responsible for hemolytic anemia is of the IgG class, occurs
201
This sequence may result in a burst of hemolysis with hemoglobinuria. less frequently than the IgM antibody, and may be directed against the
31
Combinations of these clinical patterns also occur. Cold agglutinins of benzylpenicilloyl, or, more commonly, nonbenzylpenicilloyl determi-
the IgA isotype, an isotype that does not fix complement, may cause nants. 28–30,32 Other manifestations of penicillin sensitivity usually are not
acrocyanosis but not hemolysis. Thus, the relative degree of hemolysis present.
202
or impeded RBC flow is influenced significantly by the properties and All patients receiving high doses of penicillin develop substan-
quantity of the cold agglutinins in a given patient. tial coating of RBCs with penicillin. The penicillin coating itself is not

Kaushansky_chapter 54_p0823-0846.indd 829 9/19/15 12:27 AM