Epidemiology of hemolytic disorders in Denmark

The normal red blood cell has a life span of approximately 120
days, and hemolysis defines the situation where red blood cells
are destroyed earlier. Irrespective of the underlying cause of
hemolysis, observations indicate that hemolysis in itself, and
especially the release of cell debris to the blood have some common health consequences, including thrombosis.

Congenital hemolytic disorders are endemic to former and
present malaria areas, but with growing global migration, this
geographical distribution is disrupted. The acquired hemolytic
disorders are mostly related to immune attacks on red blood
cells and are generally considered to be rare, without geographic
variations, however, this is unknown.

Probably reflecting that both acquired and congenital hemolytic
disorders are rare—particularly in high-income countries—
research in frequency and complications of hemolysis is limited.
Incidence and prevalence are, for most of the disorders, unknown. Few studies have compared complications in hemolytic
patients with non-hemolytic persons. However, survival is assumed to be reduced for many hemolytic disorders, but the
magnitude of this effect is overall unknown.

To address these gaps in knowledge, we have validated the diagnoses of hemolysis in the Danish National Patient Register
and found that the positive predictive value ranged from 70.8 to
24 91.7%. These values are sufficient to support further registerbased studies of hemolytic disorders as the exposure, even though the result from the register study also suggests some possible improvements of the validity and capture rate. These potential improvements encompassed exclusion of diagnoses solely registered at surgical departments, and the inclusion of biochemical registers to identify persons with congenital trait conditions of hemoglobin variants.

We then formed a cohort of all patients in Denmark, 1977–2016,
with at least one diagnosis of hemolysis, termed the Danish
Hemolysis Cohort. The data derives from the Danish National
Patient Register and includes information on all hospitalizations
from 1977, and from 1994 also patients registered in out-patient
hospital clinics. The health information was merged with information on migration, death, age, and sex via the unique central person register number, assigned to all persons living in Denmark. Further, census information was obtained from Statistics Denmark.

Using this cohort, we have estimated incidence and prevalence
of all acquired hemolysis during 1980–2016, and the prevalence
of all congenital hemolysis, 2000–2016. The incidence rate of
acquired hemolysis increased during the study time. The only
exception was drug-induced hemolysis, which declined in incidence rate. Autoimmune hemolysis, Evans syndrome, Cold
agglutinin disease, and Paroxysmal nocturnal hemoglobinuria
all more than doubled in overall incidence rate. The prevalence
proportion of almost all hemolytic disorders increased continuously during the study periods. The overall survival for patients did not improve significantly for the majority of the included disorders.

We then used Evans syndrome as a first model of the hemolytic
disease subtypes to survival studies, including assessment of
both overall survival and causes of death. The studies indicated
that the survival for patients with Evans syndrome is considerably reduced, and that the same probably holds true for autoimmune hemolytic anemia. The causes of death analyses showed that within the first year after diagnosis, bleeding, cardiovascular, and hematological malignancies were common causes of
death.

Overall, our studies support, that register-based studies in
hemolytic disorders are feasible; and we have identified an operational cohort of all persons with a registered diagnosis of
hemolysis in Denmark, The Danish Hemolysis Cohort. We are,
to the best of our knowledge, the first to estimate the incidence
and prevalence of all acquired hemolytic disorders in a nationwide sample, and the first to estimate the nationwide prevalence
of all congenital hemolytic disorders. Our studies of survival
indicate that acquired hemolysis is associated with decreased
survival and that future studies of survival and complications
are possible and warranted.