55 Hemolytic Anemia resulting from Immune Injury Flashcards
The two main features of immune red blood cell (RBC) injury are
- (a) shortened RBC survival in vivo and
- (b) evidence of host antibodies reactive with autologous RBCs, most frequently demonstrated by a positive direct antiglobulin test (DAT) result, also known as the Coombs test
Most cases in adults are mediated by ___________ autoantibodies.
Warm-reactive autoantibodies
Sera of some patients with hemolytic anemia directly agglutinated saline suspensions of normal or autologous human RBCs
These serum factors, later shown to be specific antibodies (largely of the immunoglobulin [Ig] M class), were termed
Direct or saline agglutinins
The patients’ sera could mediate lysis of the test RBCs in the presence of fresh serum as a complement source.
The heat-stable factors (antibodies) necessary for in vitro complement-mediated lysis were called
Hemolysins
When the RBCs are coated chiefly with complement proteins, a positive DAT result depends on the presence of anticomplement (principally ____________) in the antiglobulin reagent.
anti-C3
Cryopathic hemolytic syndromes are caused by autoantibodies that bind RBCs optimally at temperatures less than _____°C and usually less than ______°C.
Less than 37°C and usually less than 31°C
Two major types of “cold antibody” may produce AHA:
- Cold agglutinins: cold agglutinin disease; agglutinins
- Donath-Landsteiner autoantibody: paroxysmal cold hemoglobinuria; hemolysins
Immunoglobulin OR complement system
In both cryopathic syndromes, the ____________ plays a major role in RBC injury; as such, much greater potential exists for direct intravascular hemolysis than in warm antibody–mediated AHA.
Complement system
Cold agglutinin disease pertains to patients with chronic AHA in which the autoantibody directly agglutinates human RBCs at temperatures below body temperature, maximally at __________°C.
0°C–5°C
Cold agglutinins typically are Ig_____, although occasionally they may be immunoglobulins of other isotypes.
IgM
Monoclonal or Polyclonal
The cold agglutinins in chronic cold agglutinin disease generally are__________.
Monoclonal
Most cold agglutinins have specificity for _______________of the RBC
Oligosaccharide antigens (I or i)
Viral disease associated with Donath-Landsteiner antibody
Congenital or tertiary syphilis
rare
An increasing proportion of Donath-Landsteiner autoantibody-mediated hemolytic anemias occurs as a single postviral episode in children, without recurrent attacks (paroxysms).
The prognosis for such cases is excellent.
Donath-Landsteiner hemolytic anemia
When no recognizable underlying disease is present, the AHA is termed
Primary or idiopathic
Account for approximately half of all secondary warm AHA cases
Lymphocytic malignancies, particularly chronic lymphocytic leukemia (CLL) and lymphomas
The majority of AHA cases mediated by cold agglutinins have a
Clonal lymphoproliferative disorder
Without clinical or radiologic evidence of malignancy; these are considered primary
A large proportion of patients with mixed cold and warm autoantibodies have this autoimmune disease
SLE
Infections associated with AHA mediated by cold agglutinins
Infectious mononucleosis and Mycoplasma pneumoniae
Hemolysis is rare
Rarely, in children with chickenpox
Despite the frequent occurrence of immune thrombocytopenia and positive DATs in patients infected with human immunodeficiency virus (HIV), AHA is relatively rare in these patients.
Two of the mechanisms of drug-immune hemolytic anemia that involve drug-dependent antibodies
Hapten-drug adsorption and ternary complex formation
TRUE OR FALSE
Drug-related nonimmunologic protein adsorption by RBCs may result in a positive DAT without actual RBC injury.
TRUE
Drug-related nonimmunologic protein adsorption by RBCs may result in a positive DAT without actual RBC injury.
In general, AHA is considered secondary when
(a) AHA and the underlying disease occur together with greater frequency than can be accounted for by chance alone
(b) the AHA reverses simultaneously with correction of the associated disease, or
(c) AHA and the associated disease are related by evidence of immunologic aberration
Careful follow-up of patients with primary AHA is essential because hemolytic anemia may be the presenting finding in a patient who subsequently develops overt evidence of an underlying disorder.
The most common cause of drug-induced autoantibodies
Fludarabine
Replaced α-methyldopa
In warm-antibody AHA, the autoantibodies that mediate RBC destruction are predominantly (but not exclusively) ______ globulins
IgG
Although generally transient, the positive DAT result may persist for up to _____ days in some transfusion recipients, long after any transfused RBCs have disappeared.
300 days
Drug that can induce warm-reacting IgG anti-RBC autoantibodies in otherwise normal persons
α-methyldopa
A critical difference is that the drug-associated autoantibodies subside when the drug is discontinued, suggesting that
* (a) the latent potential to form this type of anti-RBC autoantibody is present in many immunologically normal individuals, and
* (b) the steps required to generate such autoantibodies do not necessarily create a sustained autoimmune state
The approximate frequency of positive DATs in the entire population
1 in 10,000
Also the prevalence of positive DATs in normal blood donors
Almost all patients with cold agglutinin disease display _______________ whose heavy-chain variable regions are encoded by ________________
Monoclonal IgM cold agglutinins (with either anti-I or anti-i specificity)
IGHV4–34 (immunoglobulin heavy chain variable region)
TRUE OR FALSE
There is a direct relationship between the quantity of RBC-bound IgG antibody and RBC survival
FALSE
There is an inverse relationship between the quantity of RBC-bound IgG antibody and RBC survival
In wAIHA, The macrophage has surface receptors for the Fc region of IgG, with preference for the:
IgG1 and IgG3 subclasses and surface receptors for opsonic fragments of C3 (C3b and C3bi) and C4b
RBC sequestration in warm-antibody AHA occurs primarily in the
Spleen
Very large quantities of RBC-bound IgG or the concurrent presence of C3b on the RBCs may favor trapping in the liver.
A consistent and diagnostically important hallmark of AHA, and the degree correlates well with the severity of hemolysis.
Spherocytosis
TRUE OR FALSE
Direct complement-mediated hemolysis with hemoglobinuria is unusual in warm-antibody AHA, even though many warm autoantibodies fix complement.
TRUE
Direct complement-mediated hemolysis with hemoglobinuria is unusual in warm-antibody AHA, even though many warm autoantibodies fix complement.
Dahil may normal na protective mechanism ang body (CD55 and CD59)
Glycosylphosphatidylinositol-linked erythrocyte membrane proteins that limit the action of autologous complement on autoantibody-coated RBCs
- Decay-accelerating factor (DAF; CD55)
- Homologous restriction factor (HRF; CD59)
Inhibits the formation and function of cell-bound C3-converting enzyme, thus indirectly limiting formation of C5-converting enzyme
DAF
Impedes C9 binding and formation of the C5b–9 membrane attack complex
HRF
The highest temperature at which these antibodies cause detectable agglutination is termed the
Thermal amplitude
Generally, patients with cold agglutinins with higher thermal amplitudes have a greater risk for cold agglutinin disease.
The pathogenicity of a cold agglutinin depends on its ability to bind host RBCs and to activate complement. This process is called
Complement fixation
The great preponderance of cold agglutinin molecules are IgM (pentamers or hexamers)
IgM pentamers
Although in vitro agglutination of the RBCs may be maximal at 0°–5°C, complement fixation by these antibodies may occur optimally at 20°–25°C and may be significant at even higher physiologic temperatures.
TRUE OR FALSE
Pentamers fix complement and lyse RBCs more efficiently than do hexamers, suggesting that pentameric IgM plays a role in the pathogenesis of hemolysis in these patients.
FALSE
Hexamers fix complement and lyse RBCs more efficiently than do pentamers, suggesting that hexameric IgM plays a role in the pathogenesis of hemolysis in these patients.
Cold agglutinins of the____ isotype, an isotype that does not fix complement, may cause acrocyanosis but not hemolysis.
IgA isotype
A:A IgA:Acrocyanosis
Complement fixation by cold agglutinins may effect RBC injury by two major mechanisms:
(a) Direct lysis and
(b) Opsonization for hepatic and splenic macrophages
