Data examined confirm that IVIG-associated hemolysis predominantly occurs following infusion of high IVIG doses, and can affect patients at every age of both genders. While presence of hemagglutinins appears to play a major role in pathogenesis of hemolytic disorders, high hemagglutinin titers of IVIG products themselves seem to be of less relevance, indicating that the pathomechanism of IVIG-associated hemolysis may be related to the presence, but not the absolute amount, of hemagglutinins. Patients with hemolysis had additional hemolytic risks such as multiple comorbidities and medication use. IG-treated patients with multiple risks should be closely monitored for hemolysis.

Excluding donors with high anti-A and anti-B titers has minimal impact on the finished IVIG product titers due to ABO antibody neutralization and the dilution factor in the manufacturing pool.

Hemolysis associated with GGL or GGSD can occur even with low loading doses of isohemagglutinins. Data presented do not indicate that high isohemagglutinin titers of IG products play a major role in the development of these events.

Compound 48/80 has p r e v i o u s l y been shown t o improve wound h e a l i n g i n r a t s , presumably t h r o u g h s t i m u l a t i o n o f h i s t i d i n e decarboxyl ase a c t i v i t y and m o b i l i z a t i o n o f h i s t a m i n e from mast c e l l s . I n t h e p r e s e n t s t u d y , C57B1/6 mice were wounded by d o r s a l s k i n i n c i s i o n f o l l o w e d by t r e a t m e n t w i t h compound 48/80, exogenous h i s t a m i n e , o r t h e combination o f 48/80 p l u s h i s t a m i n e . S k i n -b r e a k i n g s t r e n g t h was s i g n i f i c a n t l y increased over s a l i n e -i n j e c t e d c o n t r o l s by t h e combined t r e a t m e n t w i t h 48/80 and h i s t a m i n e . N e i t h e r 48/80 o r h i s t a m i n e alone had any i n f l u e n c e on wound h e a l i n g . Histamine c o n t e n t o f s k i n a t t h e wound s i t e was s i g n i f i c a n t l y reduced by 48/80 t r e a t m e n t , b u t was u n a f f e c t e d by 48/80 p l u s h i s t a m i n e o r h i s t a m i n e g i v e n alone. I n c o n t r a s t , stomach and l e g muscle h i s t a m i n e l e v e l s were s i g n i f i c a n t l y increased beyond those of unwounded, wounded s a l i n e -o r 4 8 / 8 0 -i n j e c t e d mice. These r e s u l t s were a l s o c o n f i r m e d i n CD mice, and a r e i n c o n t r a s t t o f i n d i n g s i n r a t s i n which t r e a t m e n t w i t h 48/80 alone s i g n i f i c a n t l y improved wound h e a l i n g o f s i m i l a r l y i n j u r e d animals. 10. Greene SM, M a r g o l i s FL, G r i l l o M, F i s h e r H. Enhanced c a r n o s i n e (8-a1 any1 -L -h i s t i d i n e ) breakdown and h i stami ne metabol i sm f o l 1 owing t r e a t m e n t w i t h compound 48/80. Eur J Pharmacol 99:79-84, 1984.

In contrast to previously published data, AM was observed in both low-dose and high-dose regimens without favoring high IG doses, and females were affected nearly four times more often than males. Immunoglobulin G dimers may play a role in the etiology of AM, and subcutaneous administration may be associated with a lower rate of AM compared with intravenous administration.

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