Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

VI. Inherited Disorders of RBCs
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receptors ( Lutz et al. , 1991 ). Senescent dog RBCs accumulate
surface-associated immunoglobulin, which is believed to
promote their removal by macrophages ( Rettig et al. , 1999 ).
The relative importance of the immune- and nonimmunemediated
phagocytosis of senescent RBCs remains to be
clarified.
C . Anemia of the Newborn
Animals are generally born with hematocrits near values
for adults. Following birth, there is a rapid decrease in
hematocrit that is followed by a gradual increase to adult
values ( Jain, 1986 ). Factors involved to variable degrees in
the development of the anemia of the newborn include the
following: (1) absorption of colostral proteins during the
first day of life, which increases plasma volume through an
osmotic effect ( Harvey et al. , 1987 ; Mollerberg et al. , 1975 );
(2) decreased RBC production during the early neonatal
period; (3) shortened life span of RBCs formed in utero
( Kim and Luthra, 1977 ; Landaw, 1988 ; Lee et al. , 1976 ;
Mueggler et al. , 1979 ); and (4) rapid growth with hemodilution
resulting from expansion of total plasma volumes more
rapidly than total RBC mass ( Mueggler et al. , 1979 ).
In some species, production of RBCs is decreased because
of low Epo concentrations at birth ( Halvorsen and Halvorsen,
1974 ; Huisman et al. , 1969 ; Meberg, 1980 ; Meberg
et al. , 1980 ; Schwartz and Gill, 1983 ). The decreased stimulus
for Epo production may occur as a result of a placental
blood transfusion that increases RBC mass immediately
after birth ( Rossdale and Ricketts, 1980 ), a rapid increase in
pO 2 associated with breathing air, and an increase in P 50 as
discussed previously.
Much of the postnatal anemia of dogs occurs as a physiological
response to increased RBC 2,3DPG and subsequent
improved oxygen transport ( Mueggler et al. , 1981 ). The
“ anemia ” of childhood in humans is also associated with
RBC 2,3DPG above adult values. In children this increase
appears to occur secondarily to increased plasma P i concentrations
( Card and Brain, 1973 ). Serum P i values are also
above adult values in young dogs ( Pickrell et al. , 1974 ).
Although not involved in the early, rapid decrease in
hematocrit, iron availability may limit the response to
anemia in some rapidly growing animals ( Chausow and
Czarnecki-Maulden, 1987 ; Dhindsa et al. , 1971 ; Harvey
et al. , 1987 ; Holman and Drew, 1966 ; Mollerberg et al. ,
1975 ; Siimes et al. , 1980 ; Weiser and Kociba, 1983b ).
VI . INHERITED DISORDERS OF RBCS
Many hereditary disorders of RBCs have been described in
humans, but a limited number of inherited RBC disorders
have been identified in laboratory and domestic animals.
RBC enzyme deficiencies in dogs, cats, and horses have
recently been reviewed ( Harvey, 2006 ). Congenital porphyrias
are discussed elsewhere in this volume (Chapter 8) .
A . Cytosolic Enzyme Deficiencies
1 . Phosphofructokinase Defi ciency in Dogs
Autosomal recessive inherited PFK deficiency occurs in
English springer spaniel ( Giger et al. , 1985 ; Giger and
Harvey, 1987 ; Harvey and Giger, 1991 ), American cocker
spaniel ( Giger et al. , 1992 ), mixed-breed (Giger, 2000 ),
whippet ( Hayes et al. , 2007 ), and wachtelhund (Tvedten and
Rowe, 2007) dogs. Canine PFK is genetically controlled by
three separate loci. They code for muscle (M)-, liver (L)-, and
platelet (P)-type subunits ( Vora et al. , 1985 ). Random tetramerization
of the subunits produces various isozymes. PFK
in normal dog RBCs consists of 86% M-type, 2% L-type,
and 12% P-type subunits, and normal dog muscle is composed
exclusively of M-type subunits ( Mhaskar et al. , 1992 ).
Studies of brain and RBCs from homozygous-deficient
dogs indicated that native M-type subunits were not present,
but small amounts of a structurally unstable truncated
M-type subunit were found ( Mhaskar et al. , 1991, 1992 ).
A single mutation in the M-type gene of deficient dogs
converted a tryptophan codon to a stop codon, resulting in
a loss of 40 amino acid residues ( Smith et al. , 1996 ). As
would be expected from the subunit composition of normal
tissues, total RBC and muscle PFK activities are markedly
reduced in affected dogs ( Giger and Harvey, 1987 ; Vora
et al. , 1985 ). Changes in concentrations of glycolytic intermediates
in muscle and RBCs reflect the block at the PFK
step ( Harvey et al. , 1992a, 1992b ). RBCs from affected
dogs also exhibit altered enzyme kinetic properties because
of the loss of the M-type subunit ( Harvey et al. , 1992b ).
Homozygously affected dogs have persistent compensated
hemolytic anemias and sporadic episodes of intravascular
hemolysis with hemoglobinuria ( Giger et al. ,
1985 ; Giger and Harvey, 1987 ; Harvey and Giger, 1991 ;
Skibild et al. , 2001 ). RBC mean cell volumes are usually
between 80 and 90fl. Reticulocyte counts are generally
between 10% and 30%, with hematocrit values between
30% and 40% ( Harvey and Smith, 1994 ), except during
hemolytic crises when the hematocrit may decrease to 15%
or less. Lethargy, weakness, pale or icteric mucous membranes,
mild hepatosplenomegaly, muscle wasting, and
fever as high as 41°C may occur during hemolytic crises
( Giger and Harvey, 1987 ).
Hemolytic crises occur secondary to hyperventilationinduced
alkalemia in vivo , and PFK-deficient dog RBCs
are extremely alkaline fragile in vitro (Giger and Harvey,
1987 ). For unknown reasons, normal dog RBCs are more
alkaline fragile than those of humans and other mammals
studied ( Iampietro et al. , 1967 ; Waddell, 1956 ). The even
greater alkaline fragility of PFK-deficient dog RBCs results
from decreased 2,3DPG, which is formed below the PFK
reaction ( Harvey et al. , 1988 ). Because 2,3DPG is the major
impermeant anion in dog RBCs, a substantial decrease in its
concentration results in a higher intracellular pH ( Hladky
and Rink, 1977 ) and thereby greater alkaline fragility than