THE PHYSIOLOGICAL PATHOLOGY OP MALARIA 
227 
ocytosis of parasitized- erythrocytes. The 
hematin which is liberated into the blood 
plasma may be a factor in causing the 
malarial paroxysm since Brown (1912) 
showed that alkaline hematin injected 
intravenously into experimental animals 
caused a similar paroxysm. He also re¬ 
ported (Brown 1913a, 1913b; Brown and 
Loevenhart 1913) that hematin produced 
pathological changes in the blood, circula¬ 
tion and kidneys somewhat comparable to 
those seen in malignant malaria. 
Hematin probably acts as one of the 
stimulants to the reticulo-endothelial sys¬ 
tem in malaria. It may also produce a 
blocking effect on the reticulo-endothelial 
system, such as is produced by the intra¬ 
venous injection of inert particulate mat¬ 
ter, and may thereby produce a disfunction 
as well as a hyperfunction of these cells. 
Hemoglobin. Probably not all of the 
hemoglobin in parasitized erythrocytes is 
changed into hematin by the time the ma¬ 
ture schizonts rupture the erythrocytes, 
and consequently some of it is probably 
liberated into the blood plasma. It is not 
ordinarily detectable in the blood plasma 
in malaria because of its rapid transfor¬ 
mation by the reticulo-endothelial cells into 
bilirubin with the liberation of iron. The 
bilirubin is quickly discharged into the 
blood plasma and in heavy malarial infec¬ 
tions is detectable there in considerable 
quantities, producing an indirect Van den 
Bergh reaction. It is absorbed by the 
parenchymatous cells of the liver and 
secreted in the bile. In excessive amounts 
it probably contributes to disfunction of 
the liver and constitutes an important part 
of the thickened bile which may be respon¬ 
sible for the so-called bilious symptoms of 
some severe cases of malaria. 
If the iron from the hemoglobin is not 
immediately utilized in the reformation of 
new hemoglobin, it may be found in the 
form of hemosiderin in the parenchyma¬ 
tous cells of the liver, kidneys and other 
organs. 
In blackwater fever, where a sudden 
massive hemolysis of the erythrocytes oc¬ 
curs, hemoglobin is found in the blood 
plasma in large quantities. Since it has a 
fairly low threshold of excretion in the 
kidneys some of it escapes by this route. 
Most of it, however, is quickly changed to 
bilirubin by the reticulo-endothelial cells. 
It is not the province of this paper to deal 
with blackwater fever, but since there are 
many cases of malaria in which a small 
degree of hemolysis occurs without the clin¬ 
ical picture of blackwater fever it seems 
desirable to call attention to another 
change which may take place in the hemo¬ 
globin liberated into the blood plasma. 
Fairley and Bromfield (1934) discovered a 
pigment very similar to methemoglobin in 
the blood plasma of a case of blackwater 
fever. They first called this pigment 
pseudomethemoglobin; later they found 
that it did not contain globin but was a 
combination of hematin with crystalbumin, 
an albumin found in the sera of only man 
and monkeys, and renamed it methemal- 
bumin (Fairley 1938). Further investiga¬ 
tions by these authors (Fairley and Brom¬ 
field 1937) and by Foy and Kondi (1938) 
showed that this pigment occurred in the 
plasma of most of the cases of blackwater 
fever which they studied and that methe¬ 
moglobin, which was previously supposed 
to be the brown pigment present in the 
serum of these cases, did not occur in the 
plasma but was formed in the urine as a 
product of hemoglobin. Methemalbumin is 
never excreted in the urine, apparently be¬ 
cause of the large size of its molecule. 
Red Blood Cells 
The progressive anemia produced by ma¬ 
larial infection is usually of the secondary 
type with evidence of normal or stimulated 
functioning of the bone marrow, although 
in some cases of chronic infection both with 
P. falciparum and P. vivax a primary type 
of anemia has been described. The two 
conditions usually can be differentiated in 
the blood itself by the Price Jones curve 
for measuring the diameters of the cells 
(Fairley and Bromfield 1933). With the 
progressive reduction in erythrocytes, the 
oxygen carrying capacity of the blood is 
reduced and this, of course, interferes with 
